Iron-catalyzed synthesis of N-heterocycles via intermolecular and intramolecular cyclization reactions: A review

2.1 From carbonyl compounds

In important pharmaceutical and natural products, nitrogen-containing heterocycles are preferred scaffolds (Hazelard et al., 2017; Trowbridge et al., 2020; Ricci, 2008). The accessibility and ecofriendly nature of iron catalysts provide nitrene insertion which is the utmost intriguing way to C-H amination (Wang and Deng, 2018; Plietker and Röske, 2019; Liu, 2019; Liu, 2020).

Zhong et al., developed in situ intramolecular amidations of N-benzoyloxyureas by using iron-catalyst [Fe(OTf)₂] and bipyridine without employing extrinsic oxidants. Using aliphatic C(sp³)-H amidation, a variety of cyclic ureas are produced in high yields. Cyclic urea (2) was synthesized by using N-benzoyloxylurea (1) as a substrate and10 mol% of FeCl₂ as a catalyst in the presence of ligands such as bipyridine (L₁), K₂CO₃ as a base, and acetonitrile at the temperature of 40 °C for 6 h. A variety of substituents like halogens at the para-position of the phenyl group and the electron-rich groups were well tolerated in good to high yields. A precursor having a nitro group containing an electron-withdrawing group afforded product in lesser yield (71%) (Scheme 1) (Zhong, 2021).

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Scheme 1

Intramolecular amidation of N-benzoyloxyureas by using iron-catalyst.

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Furthermore, numerous naturally produced alkaloids and biologically active compounds contain benzo[b]carbazoles, a form of polycyclic structure (Miller and McCarthy, 2012; May and Moody, 1984; Asche, 2005; Hande, 2008; Ramkumar and Nagarajan, 2014; Schmidt et al., 2012). Because of its chemiluminescent and optoelectronic capabilities, the coplanar structure of these molecules offers a wide range of applications in materials science (Wu, 2005; Levick, 2012; Levick, 2014; Bałczewski et al., 2012). Pericyclic reactions have historically been thought of as a cost-effective way to create bonds and are most common in tandem reactions (Sankararaman and Reactions-A, 2005; Qin, 2020; Arns and Barriault, 2007; Poulin et al., 2009). The exo-dig cyclization of alkynes by using iron-catalyst produces a reactive intermediate of vinylidene, which is then trapped in a pericyclic reaction to produce benzo[b]carbazoles from certain substrates in one step (Anderson, 2011; Nicolaou and Chen, 2009; Wang, 2011; Grigg, 2006).

The corresponding benzo[b]carbazoles (4) were synthesized by using aroyl substrate (3) catalyzed by 20 mol% Fe(OTf)₂ at 130 °C temperature. The reaction went well for a wide range of 5H-benzo[b]carbazoles (4) by using aroyl moieties in R¹ (electron-donating), R² replaced with chloro, fluoro, methyl, and R³ with both electron-rich or poor groups in moderate yields (Scheme 2).

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Scheme 2

Iron-catalyzed synthesis of benzo[b]carbazoles by using aroyl substrates.

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The carbonyl group of the benzoyl moieties (3) has transformed into its enolic form (5), and alkyne has been coupled by Lewis acid, allowing for a 5-exo-dig cyclization and consequent proto demetallation, generating intermediate (6) of vinylidene. Intermediate (6) has transformed to its enolic form (7) and 6-π electrocyclization produced intermediate (8), whereas aromatization by aerial oxidation produced the hydroxy-5H-benzo[b]carbazole intermediate (3a). When the oxygen of sulfonyl intermediate (3a) interacted with Fe(OTf)₂, the intermediate (9) was formed, and the five-membered intermediate (10) has been formed by the successive nucleophilic interaction of phenolic OH. Finally, by rearranging intermediate (10), the desired product (4) has been obtained, and the catalyst has been recycled for the next process (Scheme 3) (Boominathan, 2015).

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Scheme 3

Mechanistic pathway for the synthesis of benzo[b]carbazoles.

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Loup and Coworkers reported indoles are synthesized by the reductive cyclization of ortho-vinylanilides which catalyze by a stable iron complex at room temperature (Andersson and Munslow, 2008; Trost and Ball, 2005; Gribble, 2010; Kaushik, 2013). The reaction yields through the vinyl group hydromagnesiation and trapped in situ produced benzyl carbanion by an intramolecular electrophile.

Herein, the corresponding indoles (12) were synthesized by using derivatives of benzamides (11) catalyzed by an iron catalyst such as Fe₁ = [PrBIPFeCl₂] (BIP = bis(min))pyridine) (10 mol%) and EtMgBr in Et₂O, THF at rt. for 1 h. A wide variety of benzamides (11) consisting of electron-rich and withdrawal groups were synthesized 2-arylindoles (12) in affordable yield (Scheme 4).

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Scheme 4

Synthesis of substituted indoles using an iron catalyst.

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The following has the process of making an indole: Intermediate (17) has produced by hydromagnesiation of the selective iron catalyst. The in situ produced benzyl carbanion can attack an amide substrate, affording intermediates (18 or 19). Based on control testing, the above step appears a significant Grignard reaction that may not require an iron catalyst. Finally, after the water operation, the intermediate (20) has available, which can easily be shortened and refined to produce indole (12). However, the method that requires protonation (18) cannot be completely removed. Intermediates connected to both (20) and (18) have been previously proposed or found to be intermediate in multi-step indole synthesis (Scheme 5) (Lautens et al., 2021).

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Scheme 5

Mechanistic pathway for the synthesis of substituted indoles.

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Furthermore, Imidazolinone is a key heterocyclic structure found in a variety of bioactive compounds. A novel catalytic system made up of FeCl₂ and β-discriminate ligand may convert α-azidyl amide intermediates to synthesis imidazolinone by the intramolecular C(sp³)-H amination (King et al., 2011; Iovan and Betley, 2016; Wilding et al., 2017; Huang and Che, 2015; Liu, 2013). Azides are a frequent supply of nitrogen for this purpose (Bräse, 2005; Intrieri, 2014; Shin et al., 2015).

The 2-azido-N,N-diarylmethyl-2-methylpropanamides (21) react in presence of ligand β–diketiminate such as L₂ = [N((4E,2Z)-4-(mesitylimino)pent-2-en-2-yl)-2,4,6-trimethylaniline] to produced imidazolinone (22) by using iron catalyst such as FeCl₂ (20 mol%) at 100 °C for 12 h. The reaction went well for the series of 2-azido-N,N-diarylmethyl, 2-methyl propanamides but the benzyl ring substituent had a little consequence on the reaction (not affect the selectivity). The yields of desired compounds were good to fair (Scheme 6).

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Scheme 6

Synthesis of imidazolinone by using FeCl₂ as a catalyst.

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There has been presented a probable mechanism: The in situ generated NacNacFe^II complex (23) combines with the precursor to produce radical of ferric-iminyl complex (24), which has subsequently been subjected to intramolecular hydrogen atom transfer (HAT) to yield intermediary (26). A quick radical interaction converts the intermediate (26) to product imidazolinone (22). Apart from this route, the reactions might also continue through the reasonably stable ferric-imido intermediate (25) by direct C-H inclusion (path B). Because no precursors could be identified and defined, these two pathways could not be differentiated at this time (Scheme 7) (Zhao, 2019).

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Scheme 7

Mechanistic pathway for the synthesis of imidazolinone.

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Furthermore, the earth-abundant transition metal of the first row (iron) is non-toxic metal, which is attractive from an economic, environmental, and health perspective (Gandeepan, 2018; Bolm, 2009; Chirik and Morris, 2015; Beller, 2019). The simple transformation of nitrogen-containing benzoyloxyureas to 2-imidazolidones, which are significant scaffolds in bioactive chemicals, is catalyzed by ferrous chloride in conjunction with 1,10-o-phenanthroline (Patocka, 2020; Borsini, 2002). The C-H amination of propargylic, benzylic, allylic, and fully inactivated aliphatic C(sp³/sp²)-H bonds occur under mild circumstances such as accessible ligand without an inert environment or dry solvents by employing a simple iron salt (van Vliet and de Bruin, 2020; Shimbayashi, 2019).

The reaction conditions for the synthesis of 2-imidazolidones (28) were N-benzoyloxyureas (27) as a substrate by using the catalyst of iron such as FeCl₂·4H₂O (0.02 mmol), 1,10-o-phenanthroline, MeCN, and Na₂CO₃ at 50 °C for 14 h. The amination(C-H) of benzylic C(sp³)-H bonds, tolerates a wide range of nitrogen derivatives at the benzoyloxyureas, as well as various groups of alkyl, and also trimethylsilyl methyl. In the phenyl moiety at para-position, both substituents electron-poor and rich were effectively transformed. The C-H amination of propargylic, allylic and 2°/3° aliphatic C(sp³)-H bonds were effectively synthesized respective 2-imidazolidones (28) in fair to good yields (68–95%) (Scheme 8).

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Scheme 8

Iron catalyzed synthesis of imidazolidin-2-ones.

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The active catalyst of Fe^II attached to the 1,10-Phenanthroline ligands which correlate to the nitrogen-containing benzoyloxyurea, and an intermediate iron nitrenoid (29) has generated after deprotonation of the N-H group and then leaving group benzoate has released. In its triplet state, the intermediate iron nitrenoid proceeds through a 1,5-hydrogen atom transfer (HAT) to produce a radical intermediate (30), which has proceeded by a fast rebound of radical to form a newly C-N bond (31). The iron catalyst has been regenerated after the formation of imidazolidin-2-ones (28) for the further catalytic cycle (Scheme 9) (Jarrige, 2021).

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Scheme 9

Mechanistic pathway for the synthesis of imidazolidin-2-ones.

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Fe^III(TPP)Cl is a biocompatible, non-toxic, and inexpensive iron catalyst for the aromatic amidation of (sp²)C-H via cyclization of substrates such as N-Tosyloxyarylcarbamate intramolecularly under mild conditions (low catalyst loading, room temperature, external free oxidant, and water-soluble side product) to biologically important benzoxazolones (Liu et al., 2010; Liu, 2015; Singh et al., 2016; Prasanthi, 2018; Hennessy and Betley, 2013; Poupaert et al., 2005; Bach, 2015).

Benzoxazolones (33) were synthesized by using N-tosyloxyarylcarbamates (32) as substrate by using an iron catalyst such as Fe^III(TPP)Cl (2 mol%) at the temperature of 25 °C for 6–12 h. N-tosyloxyarylcarbamates were well tolerated with diverse substrates such as aryl, alkyl, alkoxy, and halogen groups. The electronic effect was observed on 4-substituted-carbamate in which electron-poor substituents provided reduced yields whereas electron-donating substituents (Me, alkoxy) provide good to excellent yields (Scheme 10).

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Scheme 10

Intramolecular C(sp²)–H amidation of N-tosyloxyaryl carbamates by using an iron(III) catalyst.

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The N-Tosyloxy carbamate (32) initially coordinates with Fe^III-porphyrin resulting in the intermediate of Fe^V–nitrenoid (34), then by stepwise electrophilic substitution undergoes nitrenoid insertion by aromatic C-H bond via an intermediate of arenium-ion (35) to give the corresponding benzoxazolones (33) (Scheme 11) (Prasanthi, 2018).

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Scheme 11

Mechanistic pathway for the synthesis of Benzoxazolones.

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2.2 From esters

Nitrogen containing heterocycles of sulfamate esters are frequent moieties in synthetic organic intermediates, agrochemicals and pharmaceutics (Hazelard et al., 2017; Roose, 2015; Córdova et al., 2007). Intramolecular C-H amination by using iron-catalyst of sulfamate-esters utilizing simple and inexpensive ligands. The reaction is accelerated by the addition of a second ligand(bipyridine) which also increase the yield (Zhang et al., 2014).

The aliphatic substrates of sulfamate ester (36) with the iron catalyst such as Fe(ClO₄)₂ (10 mol%) in the presence of ligand (L₁) bipyridine in CH₃CN, and C₆H₅I(OCO₂CF₃) at the temperature of 80 °C for the production of desired N-heterocycle products. The allylic C-H bonds and various benzylic derivatives including both electron-poor and rich substrates were aminated in excellent yield (54–78%). Secondary alcohol-derived sulfamate esters (37) were functionalized in high yield (Scheme 12) (Liu, 2019).

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Scheme 12

Intramolecular C-H amination of sulfamate esters catalyzed by iron.

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2.3 From sulfonamide

Sultams (cyclic sulfonamides) are the preferred scaffold of pharmaceutics and agrochemicals because of their extensive range of bioactivities. Direct synthesis of cyclic sulfonamides in the presence of ligand (amino pyridine) by using iron catalyst through intramolecular amidation of C-H(sp³). This method features an accessible catalyst and tolerates a wide range of substrates (Drews, 2000; Scozzafava, 2003; Scott and Njardarson, 2019; Feng, 2016; Inagaki, 2000; Donkor, 2000; Wells, 2001; Lad, 2017; Zhuang, 2003; Fejerman, 2012; Poutsiaka, 1961).

The reaction conditions for the synthesis of sultams (39) were 3-phenylpropane-1-sulfonamide (38) as a standard substrate by using a catalyst such as Fe(ClO₄)₂ (10 mol%) and ligand such as L₃ = N-methyl-1,(pyridine-2-yl)-N-(pyridine-2-ylmethyl)methenamine at the temperature of 80 °C for 2 h. Substituents at the para-position of the aromatic ring, containing both electron-deficient and rich moieties yielded the required ɣ-sultams in moderate to fair (52–88%) yields. In meta and ortho-positions substituents of the aromatic ring were likewise tolerated, afforded good (61–89%) yields of the respective products (Scheme 13) (Zhong, 2019).

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Scheme 13

Intramolecular C-H(sp³) amidation by using an iron catalyst.

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2.4 From halides

5,10-Diaryl-5, 10-dihydrophenazines (DADHAPs) are important moieties of organic luminescent materials, have magnetic properties, and use as photoredox catalysts. The one-pot DADHPs synthesis from diphenylamines with new Fe-catalyzed amination of the C-F process was developed. The catalytic FeCl₂ and 1,2-dibromoethane stoichiometric, homo-dimerization of magnesium diarylamides along with defluorinated cyclization intramolecularly (double-ortho C-F amination), yielding the corresponding DADHPs with perfect regio-control (Okamoto, 2003; Zhang, 2014; Lee, 2015; Theriot, 2016; Lim, 2017; Ramsey, 2017).

The synthesis of DADHP (41) by tandem intramolecular C − F amination using the amine substrate such as 2-fluoro-N-phenylaniline (40) in the presence of FeCl₂ (5 mol%) as a catalyst at 100–120 °C for 12 h. The DADHP (41) synthesis was relaid on the improved process, which yielded DADHP derivatives in fair to good yields with perfect regio-selectivity. The reaction was well tolerated by various electron-withdrawing groups on the aromatic ring at different positions and also include phenazine core afforded good to excellent yield (61–91%). It is essential to know that the C-F (ortho) amination occurred regio-selectively when the fluoro group was present in the meta- and para-positions. (Scheme 14).

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Scheme 14

Synthesis of DADHP by tandem intramolecular C − F amination.

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The production of dinuclear tetra-amide iron complexes occurs before the creation of the C-N bond. The synthesis of magnesium amide dimer (42) was suggested by the substantial precipitation of MgBr₂ in the solution of magnesium diarylamide with toluene. The cyclic four-membered iron diamide complex (43) has been formed via trans-metalation of FeCl₂ with magnesium amide. The (C-F) amination occurs intermolecularly most likely through the route of SNAr to yield the iron amide complex containing the relevant o-phenylenediamine (45) which has been assisted by fluoro substituent coupling to the adjacent iron centre (44). The (C-F) amination of the benzene-1,2-diamineoccur intramolecular through the route of SNAr (46) yields the equivalent DADHP (41) in the second step. The fluoro groups improved the reactivity of SNAr reaction of the aryl ring when the substrate is 2,4-difluoro-N-phenylaniline was employed, allowing tandem C-F aminations without 1,2-dibromoethane and iron-catalyst, afforded in poor yield under the same reaction temperature and time. Although it deduces that it might oxidize the iron di-amide species to stimulate SNAr processes, the role of 1,2-dibromoethane has unknown (Scheme 15) (Aoki, 2019).

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Scheme 15

Mechanistic pathway for the synthesis of DADHP.

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2.5 From alkenes

Nitrogen-containing heterocycles of a six-membered ring may be adjacent in a variety of bioactive natural compounds, α-polyenyl-substituted piperidines being one of the most common. Micro-grewiapine A, Corydendramine A, and B and microcosamine A and B, are trisubstituted piperidines with the N- and polyenyl substituents differing only in nature (Vitaku et al., 2014; Pelletier and Joshi, 1991; O’Hagan, 2000).

The synthesis of cyclized product α-dienyl monosubstituted piperidines (48) was isolated in moderate yield from diene (47) as a substrate by using iron-catalyst such as FeCl₃·6H₂O (5 mol%) in CH₃CN at room temperature for 17 h. Terminal diene was not restricted to cyclization, on C9-C10 double bond wide range of substituted dienes were tolerated (R¹ = Me, R² = H). When the CH₃ group was replaced with a benzyl group, the yield in CH₂Cl₂ remained satisfactory (73%), but less in acetonitrile (58%). Functionalized α-dienyl-piperidines with an alkenyl tributylstannane or alkenyl iodide might be obtained by cyclizing the corresponding dienes. (Scheme 16) (Gonnard et al., 2017).

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Scheme 16

Synthesis of α-dienyl-monosubstituted piperidines by using FeCl₃·6H₂O.

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Piperidine derivatives are bioactive N-heterocycles synthesized by iron catalyst through heterocyclization in an environmentally friendly manner (Guerinot, 2010). The generalized reaction for the formation of piperidine derivatives (50) from aminoacetates (49) by using FeCl₃·6H₂O as a catalyst at room temperature for 30 min. The piperidine derivatives (50) were obtained in high amounts with great diastereoselectivity (dr = 97:3) in the preference of cis-isomer via cyclization of N-tosylamides with pentyl group having a linear side chain. For isopropyl substrates at C1, the outcome was good because only one diastereomer was produced in quantitative yield (dr > 99:1). The cyclization produced the cis-2,6-disubstituted piperidine (50) in a reasonable diastereomeric ratio (cis/trans;dr = 92:8) whenever a CH₃ substituent with a low steric demand was introduced. A benzyl derivative was likewise tolerated, indicating that R¹ group at C1 had no impact on the cyclization's result (Scheme 17) (Cornil, 2015).

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Scheme 17

Synthesis of 2,6-disubstituted-piperidine by using FeCl₃·6H₂O.

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Azidoaryl(alkenes) is catalyzed by the iron complex through intramolecular C-H direct amination into the respective indoles by using mild reaction conditions and with moderate loading of catalyst. C-H direct activation is the difficult reaction in the catalysis of organometallic (Bauer and Knölker, 2015; Yang and Huang, 2015).

The reaction conditions were 2.5 mol% of TBA[Fe] and (azidoaryl)alkenes (51) as substrates in the presence of a solvent such as 1,2-dichloroethane for the synthesis of indole derivatives (52) at 100 °C for 1 h of microwave irradiation (200 W). Electron-donating and withdrawing (azidoaryl)alkenes (51) were reactive and modify into the desired indoles in high yields. Z- and E- (azidoaryl)alkenes configurations were uniformly reactive, and indole derivatives were isolated in good yields. Moreover, even tri-substituted olefins were reactive under these conditions (Scheme 18).

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Scheme 18

Iron catalyzed synthesis of indole derivatives.

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The aryl azide reacts with the[Fe(CO)₃(NO)] anion (53) to form iron nitrene intermediate (55), with the release of N₂, which generate a partial positive charge on the ortho C-atom, as shown by the intermediate (56). For the C-N bond-forming a reaction to give (57), charge transfer from metal to ligand occurs then by 1,5-hydrogen shift the transformation of indole (58) (Scheme 19) (Alt and Plietker, 2016).

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Scheme 19

Mechanistic pathway for the synthesis of indole derivatives.

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Indoles and their derivatives have significant properties synthetically and biologically; as a result, they have attracted great attention toward synthetic approaches (Sundberg, 1996; Sharma et al., 2010; Andrea, 2018; Humphrey and Kuethe, 2006). Indoles are synthesized by intramolecular C-H iron-catalyzed amination and azidoacrylates as precursors (Liu et al., 2010; Bandini and Eichholzer, 2009).

The reaction conditions were azidoacrylate (59) as a substrate and Fe(OTf)₂ as an iron-catalyst in the solvent THF at 80 °C temperature for 24 h for the synthesis of respective indoles (60). Azido acrylates (59) with electron-rich and poor groups (halo, benzyl, and trifluoromethyl groups) at the position of para reacted well to afford the respective indoles (60) in good yields. The catalysis was successful with substrates containing a variety of substituents, regardless of their position on the aryl ring. The presence of a methoxy substituent at ortho-position had no effect, while substrates containing para and meta disubstituted aromatic groups generated only one isomer in all circumstances and the yields were good (88–99% ) (Scheme 20) (Bonnamour and Bolm, 2011).

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Scheme 20

Synthesis of indole derivatives by intramolecular C-H amination catalyzed by ferrous triflate.

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Azaindoles are bioisosteres of indoles that have exceptional properties in the field of medicinal chemistry, drug discovery, and related fields of research (Smirnov, et al., 1997; Zhao and Wang, 2010). The azaindoles use as compared to the indoles is limited due to the dearth of appropriate synthetic methods. Roy and coworkers reported an iron-catalyzed amination for the formation of N-heterocycle in which tertrazoles have amide functionality with aliphatic bonds of C(sp³)-H (Das, 2020).

The reaction of tetrazole substrates (61) with the iron catalyst of 5.0 mol% Fe(TPP)Cl at the temperature of 80–130 °C for 12–24 h for the synthesis of respective azaindoles. The electron-rich and poor groups in the pyridine ring were well tolerated, and then rearrangement of reaction occurs to afford the complex N-heterocycles in high isolated yield (Scheme 21).

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Scheme 21

Iron-catalyzed amination of tetrazole substrates.

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The process has a typical radical activation mechanism in the first step Zn reduces Fe^III(TPP)Cl by single-electron transfer for the formation of active catalytic species Fe^II(TPP) (63), which was confirmed by the red shift in the UV–visible spectra. In the next step, the N is lost to form α-Fe^III-nitrene intermediate (a), when the substrate is coordinated to generate a metal-bound complex (64). The nitrene (a) then interacts with the pendant carbon double bond to form the benzylic pyridine radical (b). Following that, 1,2-migration happened to make intermediate (63), which after the shift of 1,3-H gave us the respective product (62) and allowed the catalytic cycle to regenerate (Scheme 22) (Roy, 2021).

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Scheme 22

Mechanistic pathway for the synthesis of azaindoles.

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Alkaloids are naturally active pharmaceutical compounds that contain a nitrogen atom and are synthesized by nitrene insertion and transfer reactions. An iron catalyst such as [Fe(F₂₀TPP)Cl] is an effective catalyst for the synthesis of alkaloids including indolines, tetrahydroquinolines, indoles, quinazolinones, and dihydroquinazolinones through intramolecular C–H(sp³and sp²) amination (Liu and Che, 2010).

Indoles (67) were synthesized by following reaction conditions such as aryl azide (66) as a substrate with an iron catalyst [Fe(F₂₀TPP)Cl] (0.004 mmol) and 4A˚ molecular sieves in anhydrous ClCH₂CH₂Cl under nitrogen atmosphere. Indoles were produced in high yields from substituted methyl-α-azido-cinnamates, as well as ones with electron-deficient or rich groups. In the α-position of cinnamates, aryl nitrene was inserted and ortho-azido-cinnamates may also provide the respective indoles in fair to high yields by using iron catalysts such as [Fe(F₂₀TPP)Cl] with complete azide consumption (Scheme 23).

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Scheme 23

Iron-catalyzed synthesis of indoles through C-H amination of azides.

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The mechanism has been catalyzed by [Fe(F₂₀TPP)Cl] of the amination of C(sp²)-H bonds that may contain iron-nitrene/imido complex has very similar to the mechanism proposed for dirhodium by Driver and co-workers. In the first step, Iron-nitrene/imido complex (69) has formed by the destruction of aromatic azide (66) catalysed by [Fe(F₂₀TPP)Cl]. An intramolecular hydrogen atom abstraction mechanism might then produce a benzyl radical intermediate (70). The benzyl radical intermediate undergoes collapse for the generation of the C-N bond and collapse/rotation operations to provide a combination of trans- and cis-isomer (71) (trans: cis = 0.58:1) (Scheme 24) (Liu et al., 2010).

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Scheme 24

Mechanistic pathway for the synthesis of indoles.

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Indoles and secondary amines are preferential scaffolds of natural materials, medicines and dyes synthesized by iron^II/(EtO)₃SiH complex through the reductive alkylation via intramolecular addition of alkenes to N-H bonds of amine. The reaction is an effective method for constructing novel C-N bonds and manipulating (hetero)aromatic amines (Pirnot et al., 2016; Utsunomiya, 2003; Zhang et al., 2009; Nguyen et al., 2014; Shigehisa, 2014; Musacchio, 2017).

The reaction conditions for the synthesis of substituted indoles (73) were 0.5 mol% catalyst Fe₂ = [Cp*Fe(1,2-Ph2PC6H4S)] loading to a relative substrate such as ortho-nitrostyrene (72) in the presence of (EtO)₃SiH and THF at 60 °C for 6 h. Several derivatives of indole were synthesized in high yields and functional groups like OCH₃, Br, F, CF₃, and cyclic alkenes in the presence of nitro structures (six to eight-membered rings) were well tolerated under these conditions. The tricyclic fused indole derivatives were synthesized in high yield in 1,2-dimethoxy-ethane at 80 °C (Scheme 25) (Song, 2019).

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Scheme 25

Iron catalyzed synthesis of indole derivatives.

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Pyrrolines are significant N-heterocyclic scaffolds in the area of bioactive chemicals and naturally present products, such as the biological and pharmacological uses of β-homoprolines. Pyrrolines are synthesized from γ,δ unsaturated oxime esters by the carbonylation of radicals and the intramolecular amination of alkenes (Vitaku et al., 2014; Fukuda, 2014; Lauder, 2017; Cordero, 2013). The method includes transition-iron catalyzed activation of oxime-esters (N-O) bond to form iminyl radicals, follows by intramolecular cyclization to generate radicals of new C-atom, which are then caught by C-O and converted into the desired products (Shimbayashi, 2018; Gu, 2019; Jiang, 2015; Jiang and Studer, 2017; Chen, 2015; Su, 2015).

The reaction conditions for the synthesis of pyrrolines (75) were oxime esters (74) as substrates and methanol with iron-catalyst such as Fe(acac)₃ (5 mol%) in DCE as a solvent at 100 °C temperature for 20 h under CO (50 bar.). A wide range of aryl and heteroaryl oxime-esters (74) with both electron-deficient and rich substrates on the aryl ring in various places were tolerated to synthesized the respective products in excellent yields. Other substrates, such as thiophene and 2-naphthalene, as well as adamantine derivatives of O-benzoyl oximes, were also given desired products in good yield (Scheme 26) (Zhang, 2020).

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Scheme 26

Intramolecular amination of alkenes for the synthesis of pyrrolines.

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2.6 Miscellaneous compounds

Indole moieties can be present in a wide range of bioactive natural compounds and pharmaceutics (Shvartsberg, 2009; Brancale and Silvestri, 2007). The 2,3-disubstituted indoles synthesis is developed by using a catalytic and general approach by employing aromatic of C-H amination through FeCl₂ catalyzed opening ring of 2H-azirines. The procedure can also be used to make azaindoles (Prasanthi, 2018; Bach, 2015; Alt and Plietker, 2016).

The 2,3-disubstituted indoles (77) were formed by using 2H-azirine (76) as a substrate with the iron catalyst of 5 mol% FeCl₂ at the temperature of 70 °C for 24 h in THF. The transformation is well tolerated in a variety of functional groups including amides, cyclopropyl, CF₃, OTBS, halides, OPiv, and aryl substitution undergoes functionalization on the aromatic ring (Scheme 27).

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Scheme 27

Synthesis of 2,3-disubstituted indoles using FeCl₂ as a catalyst.

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Azirine Iron-complex (78) is formed by the immediate integration of Fe^II to the N-atom of imine 2H-azirine (76); subsequent dissociation of the C-N bond forms vinyl-imene iron-complex (79); and as a result, corresponding indole (77) are generated by a 5-centred 6-π-electrocyclization of (79) through intermediates (80). The rearrangement was most likely assisted by nitrene iron-complex (79) (Scheme 28) (Jana, 2010).

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Scheme 28

Mechanistic pathway for the synthesis of 2,3-disubstituted indoles.

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The intramolecular amination of unactivated C(sp³)-H bonds catalyzes by iron nucleophilic complex such as Bu₄N[Fe(CO)₃(NO)] (TBA[Fe]) through the activation of aryl azides to afford indoline derivatives. The amination of C(sp³)-H bonds catalyzed by two possible strategies are; C-H-aminations involving intense oxidants to create nitrenoid species or the “ oxidant-free ” procedure, which depends on azides as N-donor reagents (Shin et al., 2015; Yu and Shi, 2010; Louillat and Patureau, 2014; Jiao et al., 2016; Lee, 2017).

Treating o-tert-butyl aryl azide (81) with iron-complex Bu₄N[Fe(CO)₃(NO)] (TBA[Fe]) (2.0 mol-%) at 0.5 mmol scales in dry DMF and DCE using microwave irradiation for 1 h at 120 °C for the formation of indoline derivatives (82). Due to the instability of some of the products Boc₂O was added subsequently. Electron-withdrawing groups show improved reactivity by changing the substitution pattern proximal to the reactive C-H bond and the substitution within the aryl azide substrates had some effect on the reaction conditions, although isolated yields were moderate to excellent irrespective of the substituent's electronic nature (Scheme 29).

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Scheme 29

Activation of aryl azides for the synthesis of substituted indoline.

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The amination of C-H bond intramolecularly explained by a complementary proton transfer as the C-H bond activation and increase in the C-H acidity favoured a preferred form of 6-membered rings. The intramolecular amination of C(sp³)-H bonds in azido arylalkanes to the respective indoline derivatives has been catalyzed by the iron nucleophilic complex Bu₄N[Fe(CO)₃(NO)]. The catalyst may be made in a single step from low-cost Fe(CO)₅ on a large scale, making the technique extremely appealing from a synthetic perspective (Scheme 30) (Alt et al., 2017).

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Scheme 30

Mechanistic pathway for the synthesis of substituted indoline.

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Indoline substituents are preferred scaffolds of pharmaceuticals, natural products, and physiologically active compounds that can significantly alter a molecule's chemical, physical, and biological characteristics (Richter, 2017). Although indoline and 7-azaindoline derivatives are key elements for the development of physiologically active structures their preparation techniques differ (Chen et al., 2016). The formation of inert C(sp3)-H bonds in organic compounds is significant because it improves chemical synthesis efficiency (Dick and Sanford, 2006; Davies and Manning, 2008; Brückl, 2012; Abrams et al., 2018). Current functionalized C–H bond approaches usually need substrate pre-oxidation, directing group changes, and the use of strong oxidants, resulting in de-novo synthesis with limited generality (Lyons and Sanford, 2010; Labinger and Bercaw, 2002; Ryabov, 1990).

For the synthesis of azaindoline derivatives (84) substrate (83) was formed after the cross-coupling reaction of 8-Bromo-tetrazole and either in the presence of alkene or alkyne followed by the hydrogenation and the reaction conditions were 5.0 mol% Fe-cat. in the10.0 mol% Zn-dust and C₆H₆ at 120–150 °C temperature for 72 h. The azaindoline derivatives (84) were produced in high yields by intramolecular aminations of the substrates with strong bonds of C–H and also with different bond dissociation energies. A substrate with benzylic, inert alkyl, and homo-benzylic C–H linkages promote amination at the inert and strong C–H bonds, affording only one isomer (Scheme 31).

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Scheme 31

Intramolecular amination of C-H bond for the synthesis of azaindoline derivatives.

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The Fe^II(TPP) (85) active catalytic species are produced when Fe^III(TPP)Cl has been reduced by Zn through a single-electron transfer. Tetrazole (83) then forms a metal-bound complex (86) with the catalyst, which generates the radical intermediate (87) when the N₂ gas has been lost. The bond of C–H broke intramolecularly from the intermediate (87), which has the amination rate-limiting step, producing the intermediate (88). As a result, the intermediate (88) creates the aminated product (84) by the substitution of radical and catalytic cycle recovery (Scheme 32) (Das, 2020).

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Scheme 32

Mechanistic pathway for the synthesis of azaindoline derivatives.

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Cyclic amines such as N-heterocycles are significant elements in the formation of naturally occurring physiological active compounds, pharmacological moieties, and substances. In present chemical synthesis, the ability to manipulate traditionally non-reactive functional groupings is essential. The formation of an iron-dipyrrinato catalyst that enhances C–H aliphatic direct amination by using the reactivity of an iron-borne metal–ligand with multiple bonds. When organic azides are exposed to an iron-dipyrrinato catalyst, it generates products of cyclic amine with complex patterns in core substitution (Labinger and Bercaw, 2002; Zalatan and Du Bois, 2009).

The reaction conditions for the formation of pyrrolidines (90) were a wide range of aliphatic azide derivatives (89) in the presence of catalyst Fe₃ (20 mol%) with Boc₂O, benzene, and 65 °C temperature for 12 h. When substrates with allylic, tertiary or benzylic, C–H linkages were exposed to Fe₃ (10 mol%), the appropriate Boc-protected pyrrolidine (90) was extracted in excellent yield. It was also feasible to catalytically functionalize a 2 °C–H bond, which afforded 1-Boc-2-ethyl pyrrolidine at a less yield. The poor yield was due to the generation of undesirable linear by-products that compete with the cyclization at 2 °C–H bond. Exposure of tertiary and benzylic alcohols to trimethylsilylazide and boron trifluoride diethyl etherate, was immediately transformed to the appropriate azide (Scheme 33).

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Scheme 33

Synthesis of pyrrolidines from aliphatic azides using an iron catalyst.

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The three-step process of functionalization for the C–H bond involves (a) the alkyl azide (89) substrate oxidizing the iron-catalyst from Fe^II to Fe^III, (b) (path A) for the generation of Fe-^III amide and an alkyl radical hydrogen atom abstraction occur intramolecularly (c) (path A’) recombination of radical to synthesized the respective N-heterocycle (90). The carbon-hydrogen bond insertion directly by the intermediate of radical Fe^III-imido couldn’t be eliminated (path B). Both processes involve the coordination of substrate carbon–hydrogen bond to the active iron-imido radical. The imido-radical has been most likely found in the plane formed by the dipyrrin ligand and the iron, with significant pyrrolide-adamantyl derivatives on each side. The substrate of carbon-hydrogen bond must reach the imido-radical next to the ligand of chloride to achieve this configuration. Functionalized C–H bond has fast when this orientation has been obtained. For benzylic substrates, the incoherent intramolecular kinetic isotope effect implies a sequential process (path A). When the functionalization of stronger substrate carbon-hydrogen bonds occurred, the mechanism of reaction may switch to a (path B) direct insertion pathway. The high spin Fe-imido radical for the synthesis method of inactivated and activated aliphatic substrates of carbon-hydrogen bond with the oxidative potency of the transiently generated. This iron-based cyclization of linear azides allows for quick entrance into complicated N-heterocyclic products (90) from easily available substrates, which hasn't been possible with azide photolysis or traditional Hoffmann-Löffler Freytag methods. The techniques discussed here may be used to create various saturated, cyclic compounds (Scheme 34) (Hennessy and Betley, 2013).

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Scheme 34

Mechanistic pathway for the synthesis of pyrrolidines.

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Tetrahydropyrrolizines are produced via the cycloaddition reaction by using an iron-catalyst of disubstituted alkenes with alkene-tethered oxime esters, which is a common structural motif in bicyclic alkaloids. The process is carried out through a series of cycloaddition reactions. Intra and Intermolecular cyclization is occurred respectively with a disubstituted-alkene in a regioselective manner, with the initial synthesis of an imine moiety playing a key role (Robertson and Stevens, 2014; Robertson and Stevens, 2017).

The reaction conditions for the formation of tetrahydro pyrrolizines (93) were oxime ester (91) with a variety of disubstituted-alkenes (92) in the presence of FeSO₄·7H₂O (0.03 mmol, 5 mol%) as a catalyst, and L₄= (DTBPY) 4,4′-di-tert-butyl-2,2′-bipyridyl as a ligand with C₆H₆ at the 120 °C temperature for 12 h. The oxime-ester (91) reacted with several 1,2-disubstituted alkenes (92) containing both electron-rich and poor groups on the aromatic group at the β-position resulting in high yields of the appropriate product and arenes with deficient electrons also afforded better yield. Not only ketones but also nitrile might be useful reaction partners, resulting in high yields of tetrahydro pyrrolizines (93) (Scheme 35).

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Scheme 35

Iron-catalyzed cycloaddition reaction for the synthesis of tetrahydropyrrolizines.

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In a feasible process, iron cleaves the N-O bond of (91) to generate intermediate (95), which then undergoes 5-Exo cyclization to give (96). Intermediate (96) and the equivalent iron adduct (97) may be in equilibrium. Then, with alkene (92), a region-selective radical addition occurs, producing (98). Intermediate (98) has a single electron oxidized by Fe to generate the cation (99), which then is ionically cyclized to form bicyclic iminium (101). Alternately, cyclization of radical with an imine substituent to produce (100) before oxidation to get (101) has another possibility. The process with electron-poor alkenes reinforces this. In the catalytic system, both mechanisms compete. The ylide of azomethine intermediate (102), which may have a conventional resonance structure (103′), has then deprotonated by pivalate. Finally, at the carbanion at C(5) (104) protonated followed by deprotonation on the acyl-group at the α-position completes the process (Scheme 36) (Shimbayashi, 2018).

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Scheme 36

Mechanistic pathway for the synthesis of tetrahydropyrrolizines.

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Derivatives of Purine have various biological functions, and the core purine is employed as a key element to address a wide range of biological molecules. Derivatives of 1,3-bis(4-methoxybenzyl) pyrido[1,2-e] Purine-2,4(1H,3H)-diones were synthesized via direct amination using iron-catalyst to process on readily available 5-(pyridine-2-ylamino) pyrimidine-2,4(1H,3H)-diones and oxygen (O₂) might be utilized as an oxidase in the reaction. The approach has, chemo-selectivity and the functional group affinity towards halo groups enable post functionalized annulated ring (Legraverend and Grierson, 2006; Federico and Spalluto, 2012; Baraldi, 2011; Hollinshead, 2012; Blanchard, 2012; Shi, 2012).

The reaction conditions for the derivatives of 1,3-bis(4-methoxybenzyl)-pyrido[1,2-e] purin-2,4(1H,3H)-diones (106) were 5-(pyridine-2-ylamino) pyrimidine-2,4(1H,3H)-diones (105) as a substrate with the catalyst (FeCl₂·4H₂O (15–40 mol%) in the DMSO under O₂ atmosphere (balloon) at the temperature of 120 °C for 24–48 h. The corresponding derivatives of 1,3-bis(4-methoxybenzyl)-pyrido[1,2-e] purin-2,4(1H,3H)-diones (106) were produced in fair to moderate yields and has functional group compatible over a various functional groups (Br, Cl, COOMe, C₂H₅, CH₃, Ph). However, there was no steric impact owing to substituents at the difficult C-3 position (Me, Et, Ph) (Scheme 37).

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Scheme 37

Purine derivatives synthesized by using iron as a catalyst.

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Because the intermediate radical (107) and cation (108) have become unstable by resonance in the ring of pyridine, in this case, a radical mechanism would also be consistent with the more difficult reaction seen with electron-withdrawing groups as substituents. The difficulty in the closure of the ring affected between C5- and C3-substituted moieties with a hetero-atom (OCH₃ and Br) may have been related to hydrogen bonding intramolecularly that prevents radical production. As a result, the electronic effects of carbon-3 and 5 substituents should be comparable. Alternatively, in the instance of C3 substitution, a non-planar orientation that only has an inductive impact resulting in destabilization (steric-suppression of resonance) might explain these findings (Scheme 38) (Maes et al., 2013).

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Scheme 38

Mechanistic pathway for the synthesis of purine derivatives.

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N-heterocycles of benzothiazoles are important moieties in pharmaceutical industries. The formation of C-S bonds through oxidative direct intramolecular via functionalized carbon-hydrogen bond is an adorable method for the formation of benzothiazole. Pyridine had a critical role in the high yields and selectivities, according to preliminary mechanistic analyses (Li et al., 2007; Li et al., 2008; Wen, 2010; Li, 2009; Song, 2009; Yoshikai, 2009; Massari, 2010; Wang, 2012; Aiello, 2008).

N-aryl alkyl thioamides (110) employed as the substrate, under optimization conditions such as oxidant Na₂S₂O₈ in DMSO with (10 mol%) the iron catalyst FeCl₃ in the presence of pyridine gives the good yield of benzothiazoles (111). In good to high yields (71–92%) of N-aryl-tert-pentane thioamide with both electron-rich and poor substituents could accomplish C–S/C–H activation bond synthesized easily. When R was NHPh, a yield of 50% was achieved (Scheme 39).

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Scheme 39

Iron catalyzed synthesis of benzothiazole.

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Through the process, I, Fe^III oxidized the substrate N-phenyl benzothioamide (110) and subtraction of electron and proton to synthesize the intermediate of thionyl-radical, while Fe^III has been reduced to Fe^II. Na₂S₂O₈ reoxidized Fe^II species to regenerate Fe^III. The product 2-phenyl benzothiazole was then obtained by the process of cyclization with the intermediate of thionyl-radical by the process of oxidation with Na₂S₂O₈ (Scheme 40) (Wang, 2012).

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Scheme 40

Mechanistic pathway for the synthesis of benzothiazole.

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[Fe^III(TF₄DMAP)Cl] may effectively catalyse alkyl-azides amination of the C(sp³)-H bond intramolecularly. The reactions have good regio- and chemo-selectivity with a variety of substrate scope and are also worthwhile for the complexes of late-stage functionalization which are natural/bioactive compounds with low catalyst loadings as 1 mol%. Iron complexes are more economical and biocompatible than other transition-metal catalysts, and they frequently have distinctive catalytic activity in nitrene-insertion processes of azides (Wang and Deng, 2018; Iovan and Betley, 2016; Hennessy and Betley, 2013; Liu and Che, 2010; Che et al., 2011; Che, 2011; Zhang and Deng, 2012; Iovan, 2017; Shing, 2018; Paradine and White, 2012).

Fe₄ = [Fe^III(TDCPP)-(IMe)2]I may effectively catalyze amination of carbon-hydrogen bond intramolecularly of a wide range of alkyl-azides (112). After all, the reaction needed a 10 mol% catalyst loading to provide good substrate conversion and product yields (113). By using 3 mol% [Fe(TF₄DMAP)Cl], various alkyl azides (112) suffered C-H amination intramolecularly in 45–90% isolated yields (Scheme 41) (Du, 2019).

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Scheme 41

Intramolecular C(sp³)-H amination of alkyl azides.

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3.1 From internal alkynes

Transition-iron-catalysis is one of the most efficient techniques for constructing pyridine cores via cycloaddition [2 + 2 + 2] process of alkynes and nitrile. In comparison to other late transition metals, iron is considered an affordable, innocuous, largely non-toxic, and ubiquitous metal. Iron catalysis may successfully stimulate a variety of reactions (Bolm, 2004; Vollhardt, 1984; B nnemann, H., , 1985; Varela and Saá, 2003; Chopade and Louie, 2006; Shaaban et al., 2011; Tanaka, 2012).

Diyne (120) and cyanamide (121) were substrates that react to give 2-aminopyridine (122) and the reaction conditions were FeI₂ as a catalyst in the presence of Zn, THF, and dppp, at rt. for 24 h and use of naphthalene as internal standard. Dialkylcyanamides (121) reacted efficiently with malonate-diyne (120) to afford desired products (122) in fair to moderate yields (Scheme 42) (Wang, 2013).

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Scheme 42

Synthesis of 2-aminopyridine by using FeI₂ as a catalyst.

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Naturally, bioactive products, medicines, agrochemicals, and functional materials all include fused pyridines. They are also extremely valuable as bases, synthetic intermediates, and ligands, in chemical synthesis. As a result, much effort has gone into developing efficient ways for the formation of pyridine-fused scaffolds. Alkenes and alkyne-oximes as starting materials for an iron-catalyzed radical relay protocol provide a variety of structurally significant cyclopenta-fused pyridines, a useful substrate found in important compounds, in fair to good yields with good tolerance of functional groups. Prefatory biological research revealed that several of the pyridines have potent anti-inflammatory properties (Henry and De, , 2004; Hill, 2010).

Oxime (123) and N-benzyl maleimide (124) react under the reaction conditions such as Fe(acac)₃ and PhCO₂Na after stirring in 1,4-dioxane at 80 °C for 12 h, fused pyridines (125) are synthesized in excellent yields. The reaction tolerated both meta and para substituents well, however, the yield was reduced when an ortho methyl group was present. In the conversions, heterocycle-containing oximes showed excellent reactivity. Oxacyclopenta afforded fused-pyridine in good yield when the oxygen atom of oxime at the β-position interacted with N-benzyl maleimide (124) (Scheme 43) (Du, 2020).

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Scheme 43

Iron catalyzed synthesis of pyridine derivatives.

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Iron is a desirable catalyst source because of its availability and inexpensive. The iron complexes promote a variety of catalytic reactions. The cycloaddition of alkyne and alkynes-nitriles is catalyzed by the Fe(OAc)₂ with electron-rich groups and sterically hindered pyridyl-bisimine ligand. Several pyridine derivatives are produced in affordable yield.

The optimized reaction conditions for the synthesis of pyridine (128) were 10 mol% iron catalyst Fe(OAc)₂, bisimine (L₅), alkyne nitrile (126), and alkyne (127) in DMF, rather than DMA, at 85 °C. The Fe(OAc)₂/L₅-catalyzed cycloaddition of alkynes (127) and alkyne nitriles (126) produce moderate isolated yields of corresponding pyridine structures (128) (Scheme 44) (D’Souza et al., 2011).

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Scheme 44

Synthesis of substituted pyridine by using iron as catalyst.

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The imidazo[1,2-α]-pyridine is an important nitrogen compound since it has so many biological functions (Joule et al., 2020). The imidazo[1,2-α]-pyridine structures are found in therapeutically prescribed medications such as zolpidem, zolimidine, alpidem, necopidem, olprinone, and saripidem. There has been established effective intermolecular amino oxygenation of 2-aminopyridines by using iron-catalyst with a variety of ynals. Due to its cost-effectiveness, non-toxicity, quick accessibility, stability, extraordinary reactivity, and environmental friendliness, iron salts are established to be a plausible replacement for other metal catalysts, and significant development has been achieved (Shi, 2012; Maes et al., 2013; Li et al., 2007; Li et al., 2008).

The synthesis of 3-aroylimidazo[1,2-α]-pyridines (130) from 2-pyridinyl amine (128) and benzyl propiolaldehyde (129) under the reaction conditions such as FeCl₃ (5 mol%) as an iron-catalyst with toluene and air at 60 °C for 18 h. The 2-pyridinyl amine (128) substrates tolerate electron-deficient and rich groups on the pyridine ring which present the respective products in moderate to high yields. A nitro group-containing substrate could also provide an adequate yield. The conditions were tolerant to a variety of aromatic ring substituents. The substituent at the ortho position of the aromatic ring affected the yield (Scheme 45).

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Scheme 45

Iron-catalyzed intermolecular amino oxygenation of 2-pyridinylamines.

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Imine intermediate (131) was produced from an aldehyde by a condensation process with a 1° amine in the mechanism by using an iron-catalyst for the formation of 3-aroylimidazo[1,2-α]-pyridines (130) from 2-pyridinyl amines (128) and benzyl propiolaldehyde (129). The iron complex has then covalently linked to the ring of pyridine and the triple(sp) bond to form an intermediate (132). Following that, an intramolecular cyclization method has been used to make carbene intermediate (133). Finally, carbene oxidation with oxygen produced the corresponding product 3-aroylimidazo[1,2-α]-pyridine (130) (Scheme 46) (Bilal, 2021).

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Scheme 46

Mechanistic pathway for the synthesis of pyridine derivatives.

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2,3,4-trisubstituted and 2,3-disubstituted quinolines are effectively syntheses from substituted imines and electron-withdrawing alkynes in excellent yields using FeCl₃ promoted carbon–carbon bond formation. Iron plays a catalytic role in this reaction which is numerous on Earth and chemically stable, is progressively appealing for its environmentally benign nature and potential efficiency equivalent to that of other transition metals in a variety of domains, including C-H activation, C-H oxidation, cycloaddition, and Fe-porphyrin chemistry (Bolm, 2004; Sun et al., 2011; Möller, 2010; Ohara, 2001; Norinder, 2008; Kadish et al., 2010).

The reaction conditions were imine (134) and alkyne (135) as substrates in the presence of FeCl₃ (0.5 mmol), and dichloroethane as a solvent at the temperature of 80 °C with the blowing of air into the system for 5 h affording quinoline (136) in good yields. The amine moieties with electron-donating groups interacted efficiently with alkyne (135), producing excellent yields of quinolone (136). The addition of a halogen group to the amine or aldehyde substrate was particularly well tolerated by the reaction. Despite this, the reaction was severely suppressed by the nitro group. The fact that aliphatic aldimines generated from paraformaldehyde and aniline or other aliphatic aldehydes had decreased selectivity and produced indistinguishable compositions (Scheme 47).

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Scheme 47

Iron catalyzed synthesis of substituted quinolones.

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The production of an alkenyl carbocation (137) by iron-catalyst FeCl₃ as a Lewis acid alkynoate attacking which has been the initial step. Following that, an aromatic electrophilic substitution takes place between the alkenyl cations (137) and (134), resulting in the intermediate (138), which has a Friedel-Crafts reaction. Then, with the assistance of the chloride ion, (138) has activated by a proton to raise the carbon electro positivity of imine (136), which encourages the cyclization to form (140) with the release of FeCl₃. The formation of the intermediate (138) and subsequent cyclization has a cooperative process. Following the oxidation of (140) with FeCl₃, (136) and FeCl₂ have been produced. For the completion of the catalytic cycle, oxidized FeCl₂ has been produced by FeCl₃. Furthermore, starting with aniline, benzaldehyde, and (135) with FeCl₃, a standard three-component method for the transformation was investigated. The catalyst and (135) have been added to the mixture of in-situ after the condensation between aniline and benzaldehyde to get the corresponding quinoline (136) in excellent yields. This method has effective for assembling 2,3-substituted quinolones (136) from aromatic amines, aldehydes, and electron-poor alkynes in a systematic way (Scheme 48) (Li, 2014).

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Scheme 48

Mechanistic pathway for the synthesis of substituted quinolones.

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The quinoline nucleus is a common structural scaffold in a wide range of natural and synthetic substances with essential biological and pharmacological properties and as a result, effective synthetic methods for highly functionalized quinoline derivatives have been established. (Michael, 2004; Ito, 2004; Grougnet, 2005; Chen, 2004; Butenschön et al., 2001). FeCl₃ catalyzed with no ligand or additive, organic transformations of terminal alkynes, primary amines, and aldehydes yielded derivatives of 2,4-disubstituted-quinoline in excellent yields with great atom economy (Cao, 2009). The process would probably go via tandem oxidation/cyclization/addition/ condensation/ reactions, with water only as a side product.

The reaction conditions were alkyne (140), aldehyde (141), and amine (142) with the iron-catalyst FeCl₃ (16 mg, 0.01 mmol) in the solvent 1,2-dichloroethane (DCE) at 120 °C for 12 h under an air atmosphere for the formation of quinoline derivatives (143). The quinoline derivatives (143) were obtained in good yields from derivatives of benzaldehyde with both electron-rich and poor groups. The substrates for this simultaneous conversion were p-toluidine, p-anisidine, p-chloroaniline, and o-toluidine which afforded good yields of the appropriate products. Substituted phenylacetylenes, such as p-chloro phenylacetylene, p-methyl phenylacetylene, diphenylacetylene, and p-fluoro phenylacetylene, were also afforded to be appropriate moieties for this cyclization, and necessary products were produced in moderate yields. When aliphatic aldehyde (isobutyraldehyde) was used in the process, the desired product was afforded in less quantity (Scheme 49).

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Scheme 49

Iron-catalyzed three-component reaction for the synthesis of quinoline derivatives.

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A probable mechanism of the three-component iron-catalyzed one-pot sequential transformation of aldehyde, amine, and alkyne has been proposed: The FeCl₃ catalyst presumably has one terminal-alkynyl group due to the un-reactivity of the Fe^III alkynyl-complex. To create propargylamine, the synthesized alkynyl-complex was nucleophilically added to an imine generated in-situ from 1° amine and aldehyde. The nucleophilic intramolecular assault by the nitrogen-containing substituted benzyl ring linked to the nitrogen might be promoted by FeCl₃ as Lewis acid activating the triple bond of propargylamine. The Fe^III vinyl-complex was then decomposed to provide an intermediate of dihydroquinoline and recycled Fe-catalyst for future reactions. The produced dihydroquinoline might be further oxidized by O₂ with atmospheric oxygen to yield the quinoline product (136) (Scheme 50) (Zhang et al., 2011).

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Scheme 50

Mechanistic pathway for synthesis of quinoline derivatives.

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3.2 From terminal alkynes

Formation of quinoxalines utilizing a variety of terminal alkyne and O-phenylenediamine derivatives, in the presence of Fe₃O₄@Cu₂O.Fe₃O₄@Cu₂O-rGO nanocomposite demonstrates not only increased catalytic activity but also outstanding regenerate functionality. This is owing to its favourable features, such as high surface area, porous volume, distinctive semi-exposed structure, and increased mass transfer.

The reactions were synthesized in sealed tubes using o-phenylenediamines (141), aromatic alkynes (142), 1 mol% of Fe₃O₄@Cu₂O-rGO, and DMAP in each solution at the temperature of 70℃ for 8 h to provide corresponding quinoxalines (143) product in isolated yields. The compounds were produced in good yields from 3,4-Diaminoisole dihydrochloride and 2,4-diamino toluene with an electron-rich group and by using 4-Bromo-1,2-diaminobenzene with an electron-withdrawing group. Fe₃O₄@Cu₂O-rGO nanocomposite demonstrated greater product yields in all alkynes employed for evaluation, only one isomer was produced when OCH₃, CH₃, and Br groups were replaced in the substrates (Scheme 51) (Wang, 2015).

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Scheme 51

Iron catalyzed synthesis of quinoxalines.

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The antimicrobial, anti-inflammatory, antibacterial, and analgesic capabilities of the ring system of quinoline may be found in a wide range of medications. They also serve as valuable ligands and substrates in organic reactions. The formation of quinolone-3-carbonyl is described using an effective cascade Michael iron-catalyzed addition–cyclization of amino aromatic ortho-compounds such as O-aminoaryl ketones, O-amino benzyl alcohols, and O-amino aryl aldehydes with ynones. Using the catalyst of Iron^IIIchloride-hexahydrate in the air, the reactions undergo to generate quinolone-3-carbonyl derivatives without or with a substituent at the carbon-4 position in moderate to excellent yield (Michael, 2005; Roma, et al., 2000; Chen, 2001; Kleeman, et al., 2001; PB, V.B.N.A.P., Monga V. Jain R. Kaur S. Singh pp. Bioorg. , 2004; Nakatani et al., 2000; Nakatani et al., 2001; Nguyen, 1998; Shih, 2006).

The reactions undergo the following conditions for the formation of quinolone-3-carbonyl derivatives (146) were 2-amino benzaldehyde (144) with 1-phenylprop-2-yn-1-one (145) using 20 mol% of a catalyst such as FeCl₃·6H₂O in 1,4-dioxane at 80 °C in the presence of air for 4 h. The quinolone (146) was obtained in excellent yields by reacting ynone with an electron-rich (para-CH₃) and (-p-OMe) aromatic group with 2-amino benzaldehyde (144) (Scheme 52) (Li, 2011).

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Scheme 52

Cascade Michael iron-catalyzed addition–cyclization of o-amino aromatic compounds.

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Quinolines and their substituted structures are present in a vast variety of naturally occurring products and have a diverse range of biological functions. Many synthetic compounds with pharmacological characteristics use the quinoline skeleton as a helpful synthesis intermediate. Furthermore, these chemicals are very well ligands for making OLED phosphorescent complexes. The formation of quinoline derivatives from alkenes or alkynes and N-alkyl-anilines using oxidative iron-catalyzed coupling processes afforded a wide range of quinolones derivatives ranging from moderate to high yield (Balasubramanian and Keay, 1996; Musiol, 2010; Korivi and Cheng, 2006; Kim, 2005).

The reaction of N-alkyl aniline (147) with phenylacetylene (148) by FeCl₃ iron salts (10 mol%) with the oxidant di-tert-butyl-peroxide in the solvent of ethylene dichloride at 80 °C which was carried out in a Schlenk reaction tube for the synthesis of a variety of quinolone (149). A variety of N-alkyl-anilines (147) and derivatives of ethyne (148) was evaluated under the conventional reactions conditions in a synthetic technique for substituted quinolones (149) employing oxidative coupling reactions, and afforded a range from good to high yield. The presence of bulky moieties at para-position had no steric influence on the transformation of N-alkyl aniline (147) with different alkyne derivatives, including electron-poor or rich moieties on the aromatic ring of the alkynes (Scheme 53) (Liu, 2012).

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Scheme 53

Iron-catalyzed oxidative coupling for the synthesis of quinoline derivatives.

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Quinolines and their derivatives are present in various physiologically active natural compounds, as well as being essential raw materials in the chemicals and medicinal industries (Sawada, 2004; Strekowski, l., 2003). The three-component coupling catalyzed by FeCl₃ of amines, alkynes, and aldehydes yields quinolines simply and cost-effectively. From inexpensive and commonly accessible starting materials, a sequence of 2,4-disubstituted quinolines has been produced (Bolm, 2004; Saberi, 2013; Clark, 2014).

The reaction conditions were aldehyde (150), amine (151), alkyne (152) as a substrate, and FeCl₃ (0.1 mmol) as a catalyst with toluene at 110 °C, under an air atmosphere the desired quinoline (153) was afforded in good yields. The aldehyde (150) substrate scope was first explored using phenylacetylene and aniline as model substrates. When the aryl aldehyde had an electron-rich or poor substituent, the reactions performed easily, affording fair to good yields of the quinolones (153). Both p-toluidine and p-methoxyaniline were preferred derivatives for this reaction, and the corresponding products were afforded moderate yields. The reaction conditions were also applicable to halogen-containing anilines, yielding the desirable quinolones (153) in good to high yield. The alkynes such as substituted phenylacetylenes, heteroaromatic alkynes, and aliphatic alkynes, were all excellent substrates for this conversion, with reasonable to good yield (Scheme 54).

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Scheme 54

Three-component coupling by FeCl₃-catalyzed for the synthesis of quinolines.

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Intermediate (154) has been created by coupling imine and alkyne to Fe(III) in situ and then adding alkyne to imine to make propargylamine intermediate (155), which then undergoes intramolecular hydroarylation of alkyne to form dihydroquinoline intermediate (156). The formation of the propargylamine intermediate (155) and the following hydroarylation reaction are a coordinated process in this condition since the propargylamine has been not detected in the reaction mixture. The quinoline product (153) has been obtained after the final oxidation of C by O₂ in the air (Scheme 55) (Cao, 2009).

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Scheme 55

Mechanistic pathway for the synthesis of quinolines.

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Indoles are particularly desirable among nitrogen heterocycles since they are found in a wide range of physiologically active natural compounds, alkaloids, and medicines. Using iron^II phthalocyanine as the catalytic precursor and CO as the reductant, 3-aryl indoles from their respective nitrosoarenes and alkynes are converted into the corresponding indoles in high yield with remarkable functional group tolerance. Other reductants, such as isopropanol, can also be used to substitute CO gas (Gupta et al., 2007; Pindur and Lemster, 2001; Yang et al., 2004; Gul and Hamann, 2005; Aygun and Pindur, 2003).

The reaction conditions for the synthesis of 3-aryl indoles (159) were alkynes (157) react with (158) nitrosobenzene, Fe(Pc) (0.02 mmol,11.4 mg) as a catalyst in the presence of DCE (2 mL), CO (30 bar) at 120 °C temperature for 12 h. The substrates scope of alkynes (157) for this reaction was tested and the desired indole products were produced in good yields. In comparison to terminal alkynes with electron-withdrawing and electron-donating substitutes were found to react efficiently, and the corresponding 3-aryl indole (159) was extracted in high yields. Furthermore, functional groups containing halogen groups also tolerated well to provide required indoles in afforded yield. These indole compounds with halogen functional groups are suitable for further modification via cross-coupling reactions. However, the reaction of diphenylacetylene with nitrosobenzene produced just a trace of the desired indole product, and when the pent-1-yne was utilized as the substrate, no indole product was identified (Scheme 56) (Yin et al., 2017).

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Scheme 56

Synthesis of 3-aryl indoles by using iron(II) as a catalyst.

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3.3 From carbonyl compounds

A significant number of bioactive natural products and pharmacological molecules have benzoxazole moiety as a fundamental structural characteristic. The aerobic oxidation method is catalyzed by FeCl₃ for the production of benzoxazoles, in which FeCl₃ functions as an oxidizer and O₂ acts as an oxidant. Chemists are increasingly interested in iron as green chemistry and cost-effective catalyst. This approach has been used to synthesize JTP-426467 and has proven to be successful on a variety of substrates (Correa et al., 2008; Viirre et al., 2008; Ten Brink et al., 2004; Beller, 2004; Kawashita, 2003; Chen, 2008).

The reaction conditions were 2-aminophenol (160) and aldehyde (161) as model substrates, FeCl₃ (0.05 mmol) as a catalyst in the presence of toluene at the temperature of 110 °C, under 1 atm O₂ atmosphere for the formation of benzoxazoles (162). The reactions proceeded easily to provide the respective benzoxazoles (162) with good to excellent yields whether the aromatic aldehyde has an electron-donating group or an electron-withdrawing group. The intended benzoxazole was subsequently achieved in 88% yield when a bulky 1-naphthaldehyde was used as substrate. 4-pyridine carboxaldehyde was also compatible with the reaction, affording a 67% yield of the corresponding product (Scheme 57).

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Scheme 57

Iron catalyzed aerobic oxidation for the synthesis of benzoxazoles.

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JTP-426467, a selective antagonism for peroxisome proliferator-activated receptor, was produced using this process. From carboxylic acid (163), benzoyl chloride (164) was obtained, which was then converted into amide using 4-amino benzyl alcohol, followed by oxidation with Dess-Martin Perio-dinane to provide the related aldehyde (165). The predicted product JTP-426467 was obtained in 55% by reacting aldehyde (165) with 2-amino-4-methyl phenol under standard conditions for 48 h (Scheme 58) (Cao et al., 2010).

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Scheme 58

Synthesis of JTP-426467.

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Azolines are particularly important among them as 3-oxazolines are studied less than other chemicals in the sequence, most likely due to synthesis difficulties. By treating substituted vinyl azides with Togni's reagent and substoichiometric quantities of ferrous chloride, 2,2,2-trifluoroethyl-substituted 3-oxazolines, 3-thiazolines, and 5,6-dihydro-2H-1,3-oxazines are produced. 1,n-HAT reactions are performed by the newly produced imiyl radicals (Vitaku et al., 2014; Chen et al., 2014; Taylor, 2016; Akhtar, 2017; Reyes-Arellano et al., 2016; Capaldo and Ravelli, 2017; Nechab et al., 2014; Li, 2018; Chiba and Chen, 2014; Stateman et al., 2018; Protti et al., 2015; Chen, 2016; Jin, 2018).

The reaction conditions for the formation of 3-oxazolines (168) were 2-azidoallyl diarylmethyl ethers (166) and Togni’s trifluomethylating reagent (167) was activated by the addition of FeCl₂ (20 mol%) in the presence of dry dichloromethane (DCM) at the room temperature for 30 min. 2-azidoallyl diarylmethyl ethers (167) with two identical 4-substituted aryl groups were used as the substrate. The resultant 3-oxazolines (168) were in excellent yield (ranging from 81% to 98%) with the 4-fluoro- and 4-methyl substituents. As a result, the substituents with electron-donating function appeared to obstruct the formation of the heterocycle, likely due to excessive radical or cation stabilization. It was found that using freshly made Togni's reagent was advantageous. The aromatic substituent's placement was crucial since 3-oxazolines (168) carrying trifluoromethyl were produced in only moderate and low yields. Furthermore, thioether interacted with 3-thiazoline in a 63% yield (Scheme 59) (Terhorst, 2020).

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Scheme 59

Iron catalyzed synthesis of 3-oxazolines.

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Quinazolinone compounds are a kind of heterocyclic chemical that may be found in a wide range of natural and synthesized materials. Anti-inflammatory, anti-tubercular, antimalarial, antifungal, antidiabetic, and anticancer properties are all present in these substances. Microwave-assisted iron-catalyzed cyclization with or without ligand in water or DMF was developed as a green, quick, and effective technique for manufacturing quinazolinone derivatives from substituted 2-halo benzoic acids and amidines (Ma, 1997; Griess, 1869; Koepfli et al., 1947; Witt and Bergman, 2003; Mhaske and Argade, 2006; Connolly, 2005; Ma et al., 2005).

The reaction conditions for the synthesis of quinazolinone derivatives (171) were 2-halo benzoic acid (169) with acetamidine hydrochloride (170) as a substrate in the presence of Fe₂(acac)₃ as a catalyst with 1,2-Dimethylethylenediamine (DMEDA), Caesium carbonate (Cs₂CO₃), and Dimethylformamide (DMF). With the majority of the substrates, moderate to high yields were achieved for the synthesis of quinazolinone derivatives (171) from different substituted 2-halo benzoic acids with acetamidine and benzimidamide. Aryl chlorides < aryl bromides < aryl iodides have the relative reactivity of substituted 2-halo benzoic acids. The reactivity of substituted 2-halo benzoic acids with electron-donating groups was however greater than that of other substituted 2-halo benzoic acids (Scheme 60) (Zhang, 2009).

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Scheme 60

Microwave-assisted iron-catalyzed cyclization for the synthesis of quinazolinone.

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The reaction of aldehydes, anilines, and nitroalkanes with a catalytic quantity of Ferric chloride yielded a series of substituted quinolines. By using aza-Henry cyclization under ambient air, the reaction is a simple, efficient, one-pot, three-component domino method that obtained good yields of the products. This protocol's major features include the use of widely accessible chemicals as starting ingredients, an affordable metal catalyst, aerobic reaction conditions, tolerance of a wide variety of functional groups, and operational simplicity (Sun et al., 2011; Kim, 2005; Buchwald and Bolm, 2009; Sherry and Fürstner, 2008; Foley and Tilley, 1998; Kaminsky and Meltzer, 1968; Hosseinzadeh et al., 2017; Rossiter, 2005; Bizzarri, 2018; Bangcuyo, 2002; Tong, 2003; Nodes, 2009).

Synthesis of substituted quinolines (175) in presence of various nitroalkanes (174), the reaction conditions were anilines (172) and aldehydes (173) in the presence of 20 mol% FeCl₃ at 90 °C for 6 h. The impact of aryl aldehyde substituents was first investigated. The intended products were achieved in moderate to high yields in the majority of situations. Benzaldehydes containing electron-donating substituents like CH₃ and OCH₃, as well as electron-withdrawing substituents like F, Cl, and Br, interacted successfully to provide the respective 2-aryl quinoline derivatives. The benzaldehyde moiety's strong electron-withdrawing group, CF₃, efficiently produced the intended product without ease. The occurrence of both electron-withdrawing and electron-donating substituents in the same aniline moiety produced good yields of the quinoline derivatives (Scheme 61).

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Scheme 61

One-pot, three-component synthesis of substituted quinolines.

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The process starts with the synthesis of imine (176), which then reacts with the nitro alkane (174) to generate the aza-Henry adduct (177). The nitro group of the aza-Henry intermediate (177) has been rearranged to form another intermediate (178) with a gem hydroxyl group on nitrogen. The ortho cyclization of intermediate (178) and the elimination of HNO and H₂O form a new carbon–carbon bond with nearby carbenes (179). Finally, oxidation transformed the rearrangement of carbene dihydroquinoline to the appropriate quinolone (175) (Scheme 62) (Mahato, 2019).

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Scheme 62

Mechanistic pathway for the synthesis of substituted quinolines.

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Substituted imidazoles have been reported to have impressive bioactivities, such as antimicrobial, anti-inflammatory, anti-parasitic, antidiarrheal, platelet aggregation inhibitors, antiseizure agents, and glucagon receptor antagonism activity. The Fe₃O₄@SiO₂/bipyridinium nanocomposite (Fe₃O₄@SiO₂/BiPy₂ 2Cl^–) is used as a heterogeneous catalyst in the multi-component cyclo-condensation reaction of 1,2-dicarbonyl compounds, aldehydes, and N-containing compounds under solvent-free conditions to synthesis various multi-substituted imidazoles. Simple magnetic decantation can easily recover the catalyst, and it can be reused numerous times without reducing its catalytic activity (Uçucu et al., 2001; Chang, 2001).

The one-pot three-component condensation reaction of benzyl (180), benzaldehyde (181), and NH₄OAc as N-source was studied as a model in the presence of 0.05 g Fe₃O₄@SiO₂/BiPy₂ 2Cl– as a catalyst under solvent-free thermal conditions at 120 °C for the synthesis of multi-substituted imidazoles (182) and (183). Synthesis of a variety of 2,4,5-triaryl substituted imidazoles (182) and 1,2,4,5-tetrasubstituted imidazoles (183) with diverse steric and electronic characteristics proved the universality and synthetic extent of this coupling procedure. Aromatic aldehydes with electron-donating or electron-withdrawing substituents interacted effectively in all cases, affording the desired products in moderate to good yields in short reaction durations (Scheme 63) (Hosseini et al., 2021).

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Scheme 63

One-pot three-component condensation reaction for the synthesis of substituted imidazoles.

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Imidazoles, which have a five-member ring structure and are polar show a wide range of biologically important properties such as antagonists, biocides, plant herbicides, anti-inflammatory, anti-carcinogenic, antibacterial, muscle relaxant, and anti-tubercular activity (Shalini et al., 2010; Shaterian and Ranjbar, 2011). Fucoidan (FU), a fucose-rich sulfated polysaccharide derived from the brown algae Fucus vesiculosus, was utilized to prepare magnetic Fe₃O₄@FU in situ in this procedure. The catalytic activity of Fe₃O₄@FU was used to synthesize tri- and tetra-substituted imidazoles using three-component and four-component reactions, respectively, involving benzyl, aldehydes, NH₄OAc, and amine under reflux in ethanol (Mei, 2008; Balalaie and Arabanian, 2000).

The reaction conditions were benzyl (184), aldehydes (185), ammonium acetate (186), and aniline187 as model substrates in the presence of EtOH as a solvent and Fe₃O₄@FU nanocomposite (12 mg) as a catalyst for the synthesis of imidazoles derivatives (188). In such a reaction, both electron-donating and electron-withdrawing substitutions were present in aromatic aldehydes and anilines. While the presence of electron-donating groups resulted in lower reaction yields and the presence of electron-withdrawing groups resulted in greater yields with lower reaction durations (Scheme 64).

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Scheme 64

Iron catalyzed synthesis of imidazoles derivatives.

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The suggested mechanism for the synthesis of imidazole has benzyl (184), aldehyde (185), ammonium acetate (186), and amine (187) in four one-pot processes. Fe₃O₄@FU has been used to activate aldehyde and 1,2-diketone, and then amine has been added to the aldehydes to generate an imine intermediate, which has been attacked by ammonia (released from ammonium acetate) to form the amine intermediate (189). The amine intermediate (189), interacted with the activated carbonyl groups of benzil to produce the intermediate (190). After dehydration, the imidazole derivative (188) has been produced, followed by a 1.5H-shift (Scheme 65) (Banazadeh et al., 2020).

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Scheme 65

Mechanistic pathway for the synthesis of imidazoles derivatives.

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Ferric chloride is combined with an organic phosphonate ligand to produce an organic–metal nano-catalyst. Its catalytic activity was tested in the synthesis of heterocyclic compounds (2,4,5-trisubstituted imidazoles derivatives) under optimised conditions, and the product is produced with high efficiency and in a short time. For the production of trisubstituted imidazole derivatives, iron-phosphonate nanostructures are effective. For a variety of reasons, using iron compounds as catalysts in organic synthesis is desirable, it is the most widespread metal in the earth's crust, making it significantly less expensive than the most often utilized precious metals (Shaabani, 2009; Verma et al., 2013).

The reaction conditions were benzaldehyde (193), benzyl (192), and ammonium acetate (194) as model substrates in the presence of 0.05 g of Fe-DTPMP as a catalyst at the temperature of 100 °C for the synthesis of trisubstituted imidazoles (195). A diverse array of aromatic aldehydes interacted efficiently to produce excellent yields of 2,4,5-trisubstituted imidazoles (195). High yields of products were seen when electron-withdrawing substituents were present in the aromatic ring of the aldehydes, however, the effect was reversed when the electron-donating substituents were present. The shortest reaction time occurs with 4-N,N-dimethyl amino benzaldehyde, which can be attributed to the steric impact of the bulky group at the para position of benzaldehyde (Scheme 66).

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Scheme 66

Synthesis of trisubstituted imidazole derivatives by using an iron catalyst.

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The Fe-centre of the catalyst coordinates to the carbonyl oxygen atom of the cyclic aldehyde (193), similar to Lewis acid sites, hence activating the carbonyl carbon atom in the production of 2,4,5-trisubstituted imidazoles (195). The diamine intermediate (196) has been produced by reacting activated aldehyde with two equivalents of ammonium acetate (194). In the presence of Fe-DTPMP, this intermediate condenses with activated benzyl (192) to create intermediate (197), which then undergoes a (Vitaku et al., 2014; Łowicki and Przybylski, 2022; Petri, 2020; Pyta, 2022; Dong, 2016)-H shift to provide the trisubstituted imidazoles (195). The catalyst's tertiary amine groups assist in the elimination of protons during the water removal stage. The synthesis of tri-substituted imidazole derivatives (195) has been catalyzed by the coordination of iron and tertiary amines in the catalyst (Scheme 67) (Arpanahi and Goodajdar, 2020).

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Scheme 67

Mechanistic pathway for the synthesis of trisubstituted imidazole derivatives.

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Biocides (in particular, herbicides, fungicides, and growth regulators), powerful angiotensin-II receptor antagonists, glucagon receptor antagonists, and inhibitors of interleukin 1 and 5 lipoxygenases are all examples of substituted imidazoles (Lombardino and Wiseman, 1974; Chang and S. O’, Keefe, M. Pang, A. Rolando, WK Hagmann. , 2001). Cu^II immobilized on guanidinated epibromohydrin functionalized Fe₂O₃@TiO₂ (Fe₂O₃@TiO₂EGCu^II) is used for the synthesis of 2,4,5trisubstituted and 1,2,4,5 tetrasubstituted imidazoles via condensation reactions of numerous aldehydes with benzil and ammonium acetate or ammonium acetate and amine. Cu^II nano-catalyst Fe₂O₃@TiO₂EG is discovered to be an eco-friendly and highly effective nano-catalyst that could be readily handled, regenerated, and recycled numerous times without reducing its activity (Jahanshahi et al., 2016; Masjed, 2016; Jahanshahi and Akhlaghinia, 2017).

The reaction conditions for the synthesis of 1,2,4,5‐tetrasubstituted imidazoles (200) and 2,4,5‐trisubstituted imidazoles (201) were benzyl (198), aromatic aldehydes (199), ammonium acetate, and a selection of primary aromatic amines in the presence of γ‐Fe₂O₃@TiO₂‐EG‐Cu^II as catalyst under the solvent‐free condition at 100 °C temperature. The efficient one-pot, multi-component cyclo condensation processes produced 2,4,5-trisubstituted imidazoles (201) in good yields from a wide range of aromatic aldehydes (199) bearing both electron-donating and electron-withdrawing substituents. Remarkably, both heteroaromatic and aliphatic aldehydes produced good yields of the respective imidazoles. Electron-withdrawing substituents on the aromatic ring of aldehydes and electron-donating substituents on the aromatic ring of primary amines might almost similarly help to accelerate the condensation processes (Scheme 68).

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Scheme 68

One-pot, multi-component cyclo-condensation processes for the synthesis of 2,4,5-trisubstituted imidazoles.

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The production of aryl aldimine (203) has been thought to be the consequence of the nucleophilic reaction of ammonia nitrogen (obtained from NH₄OAc) on the activated carbonyl group of aldehyde. By enhancing the electrophilicity of the C-N on the aryl aldimine (203) toward the nucleophilic attack of ammonia or amine, the catalyst favours the production of intermediate (204). Between benzil and ammonia, there is no potential for imino ketone (202) to form. In the presence of Fe₂O₃@TiO₂EG Cu^(II), intermediate (204) compresses with benzil to form intermediate (205) or (206), which then rearranges to 2,4,5-trisubstituted imidazole (200) or 1,2,4,5-tetrasubstituted imidazole (201) via a (Vitaku et al., 2014; Dong, 2016) hydrogen shift or dehydration (Scheme 69) (Nejatianfar et al., 2018).

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Scheme 69

Mechanistic pathway for the synthesis of 2,4,5-trisubstituted imidazoles.

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An effective one-pot, three-component cascade method for the synthesis of imidazo[1,2-α]pyridines is demonstrated by utilizing a catalytic quantity of Ferric chloride. The reaction of readily accessible aldehydes with 2-aminopyridines in a combination of nitroalkane and DMF afforded a series of imidazo[1,2-α]pyridines. A sequential aza-Henry cyclization is thought to be involved in this conversion. Because of their relatively low cost, stability, quick affordability, inertness, and eco-friendly, an iron-based catalyst is demonstrated to induce a wide range of organic transformations, including cross-couplings, allylations, hydrogenations, and direct C-H bond functionalizations. In numerous medications, fused imidazoles are shown to be a significant structural scaffold. They also act as β-amyloid inhibitors, agonists of GABA and benzodiazepine receptors, and cardiotonic drugs (Sun et al., 2011; Hatakeyama, 2012; Lhassani, 1999; Humphries, 2006; Fookes, 2008).

The reaction conditions were 2-aminopyridine (207), substituted aldehyde (208) in presence of 20 mol % of FeCl₃ in a mixture of nitromethane (209), and DMF at 110 °C in the air for the synthesis of a series of imidazo[1,2-α]pyridines (210). Under the optimum reaction conditions, the electron-rich and electron-deficient aldehydes interacted successfully with different 2-aminopyridines to produce the required products in good yields. Aldehydes with an electron-donating OCH₃ group on the aromatic ring also performed well (Scheme 70).

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Scheme 70

Synthesis of substituted imidazo[1,2-α]pyridines by using an iron catalyst.

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Imine (211) has been generated through the condensation between 2-aminopyridine (215) and aldehyde (216). The introduction of nitromethane (209) to the imine results in the production of the aza-Henry product (212). FeCl₃ has been thought to have assisted these two steps by enhancing the electrophilicity of the aldehyde (216) and imine. Intermediate (212) tautomerizes to intermediate (213), which proceeds to intramolecular cyclization to yield intermediate (214). Following the removal of both water and nitroxyl, the final product (217) has been obtained (HNO). FeCl₃ can also behave as a Lewis acid, making intramolecular cyclization easier (Scheme 71) (Santra, 2014).

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Scheme 71

Mechanistic pathway for the synthesis of substituted imidazo[1,2-α]pyridines.

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Naturally substituted imidazoles, as well as their synthesized derivatives, have a diverse set of biological functions, making them appealing to organic chemists. P38 MAP kinase inhibitors, anti-inflammatory drugs, bio-fertilizers, insecticides, pesticides, anti-angiogenesis agents, and therapeutic compounds are only a few of their uses (MaGee et al., 2013; Keivanloo, 2013). The Fe₃O₄–PEG–Cu catalyst is assessed for its catalytic activity in the production of highly substituted imidazoles. The current iron catalyst is very active and environment-friendly for the production of 2,4,5-trisubstituted imidazoles and 1,2,4,5-substituted imidazoles. The catalyst has magnetic characteristics, allowing them to be rapidly separated from the reaction liquid using a simple magnet.

The reaction conditions for the synthesis of 1,2,4,5‐tetrasubstituted imidazoles (220) and 2,4,5‐trisubstituted imidazoles (221) were benzyl (218), benzaldehyde (219), aniline, NH₄OAc, 10 mol% catalyst Fe₃O₄– PEG–Cu at 110 °C temperature. Several aldehydes and amines were utilized as substrates for the synthesis of 1,2,4,5-tetrasubstituted imidazoles (220) and 2,4,5-trisubstituted imidazoles (221), with both electron-donating and electron-withdrawing substituents present on the aromatic aldehydes and primary amines, the reactions were similarly simple, affording high yields of the respective imidazoles (Scheme 72).

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Scheme 72

Iron catalyzed synthesis of substituted imidazoles.

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The Fe₃O₄–PEG–Cu catalyst enables the synthesis of highly substituted imidazoles, and the reaction proceeds through the diamine intermediate (222), which has been produced by the Cu on the surface of nanocomposites activating an aldehyde carbonyl group. The intended product has been obtained by condensing diamine with 1,2-diketone, dehydrating it, and then rearrangement through the imino intermediate (223) (Scheme 73) (Zarnegar and Safari, 2014).

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Scheme 73

Mechanistic pathway for the synthesis of substituted imidazoles.

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1,2,3-triazoles comprise the fundamental structure in a significant number of natural products, physiologically and pharmaceutically active compounds, discovering an effective technique for their synthesis has attracted organic synthesis's interest. Because of their ecologically friendly, cost-effective, easy separation with an external magnet, and reusability qualities, magnetic nanoparticles are widely exploited in organic transformations. CuFe₂O₄ nanoparticles facilitate the production of N-2-substituted 1,2,3-triazoles (Hein and Fokin, 2010; Decréau et al., 2010; Jewett and Bertozzi, 2010; Hua and Flood, 2010; Mamidyala and Finn, 2010; Hänni and Leigh, 2010; Le Droumaguet et al., 2010; Yang, 2015; Gangaprasad, 2015; Gawande et al., 2013; Baig and Varma, 2013; Gawande, 2012; Gawande, 2013; Gawande, 2013).

The reaction conditions for the formation of 1,2,3-triazoles (225) were chalcone (224), NaN₃, CuFe₂O₄ (1 equiv.) in the DMSO, at 80 °C temperature for 24 h, under air, then 2-NO₂-C₆H₄F was added to the mixture, and the reaction continued for 5 h. The varied chalcones (224) with a variety of functional groups, such as electron-withdrawing groups afforded good yield as compared to the electron-donating groups. However, most reactions went well, affording moderate to high yields of N-2-aryl-substituted 1,2,3-triazoles (225). The substituent's type and orientation in the aromatic ring (R¹ or R²) affected the yields of the corresponding products (Scheme 74).

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Scheme 74

Synthesis of 1,2,3-triazoles by using iron as a catalyst.

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Although the mechanism for this response had not evident, a possible explanation has been hypothesized based on the literature and this experiment. The reaction of sodium azide with chalcones (224) in the presence of CuFe₂O₄ yielded an intermediate (226), which was subsequently nucleophilically reacted with an aromatic halide to get the desired product (227) (Scheme 75) (Dong et al., 2016).

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Scheme 75

Mechanistic pathway for the synthesis of 1,2,3-triazoles.

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Quinazolinones are a prominent family of annulated six-membered nitrogen heterocycles found in natural compounds and synthesized medicines. The synthesis of quinazolinones occurs from methyl arenes and anthranilamides by cross-dehydrogenative coupling. The benzylic sp³ carbon C–H functionalization is accomplished under air by di-tert-Butyl peroxide, and the annulation process is completed by an amination–aerobic oxidation process catalyzed by iron. Iron is a transition metal that is affordable, nontoxic, and ecologically friendly (Bauer and Knölker, 2015; Mhaske and Argade, 2006; Hour, 2000; Henderson, 2006; Alagarsamy and Pathak, 2007).

The reaction conditions for the formation of quinazolinones (230) were 2-anthranilamide (228) with toluene (229) in the presence of iron catalyst FeCl₃·6H₂O and oxidant such as di-tert-Butyl peroxide(DTBP) with DMSO (dimethyl sulfoxide) as a solvent at the temperature of 110 °C for 40 h and air. 2-phenyl quinazolinones (230) containing N-substituents were effectively synthesized from the respective 2-amino N-substituted benzamides using a wide variety of anthranilamides (228), yields were good when less nucleophilic amides were replaced with an aryl group. Other heteroarene methyl-substituted amides, in addition to benzyl, produced the necessary compounds in good yields. Furthermore, there was no obvious variation in the substituents on the substrate's aromatic ring. The annulated products of iodide and bromide were similarly preserved which indicates that they are effective functional groups for subsequent processing (Scheme 76).

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Scheme 76

Synthesis of quinazolinones by cross-dehydrogenative coupling using iron catalyst.

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Initially, t-butoxy radicals have been produced by homolysis of di-tert-butyl peroxide (DTBP). The benzyl radical (229a) has been generated when the t-butoxy radical removes H• from the benzylic carbon of toluene. The t-butoxy benzyl ether (229)-OtBu was formed as an intermediate by combining these two radicals H• was extracted from (229)-OtBu by another t-butoxy radical, which then autolysis to generate benzaldehyde (231). The iron(III) salt may be implicated in the single-electron transfer oxidation of (229), particularly in the production of radical species. Following the production of benzaldehyde (231), it interacted with 2-anthranilamide (228), resulting in the synthesis of imine (232) with the support of the iron catalyst. The final product (233) has been obtained by annulating imine (232) by nucleophilic intramolecular amination followed by aerobic oxidation. Furthermore, direct amination of (228) by radical species (229a) or (229b) could not be eliminated. The synthesis of benzaldehyde (231) has been enhanced by exposure to air via a different mechanism. The combination of (229a) with O₂, followed by the removal of H• from the solvent, produced benzyl hydrogen peroxide in the presence of oxygen gas (229 or DMSO). Then, under the reaction parameters, benzyl hydrogen peroxide might be transformed into benzaldehyde (231). The synthesis of aldehydes, as well as the total process, was enhanced by oxygen gas in this route (Scheme 77) (Jang, 2020).

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Scheme 77

Mechanistic pathway for the synthesis of quinazolinones.

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Carboxylic acid derivatives and readily accessible o-substituted anilines synthesize 2-substituted quinazolin-4(3H)-ones from iron-catalyzed aerobic oxidative functionalization of the sp³ C-H interaction. The procedure uses a bio-friendly iron catalyst in conjunction with air as the sole oxidant or molecular oxygen to give broad and eco-friendly access to Nitrogen-heterocyclic compounds, which are abundant core units of many physiologically active pharmaceuticals and natural products (Bolm, 2004; Sun et al., 2011; Gonzalez-de-Castro et al., 2014; DeSimone, 2004; PD, L., Springthorpe B. , 2007; Wu, 2013; Wang et al., 2006; Balakumar, 2010; Chen, 2015; Yang, 2012; Nguyen et al., 2013; Jia and Li, 2014; Klein and Plietker, 2013; Majumdar, 2014).

o-Aminobenzamide (234) and aryl acetic acid (235) were the substrates for the synthesis of 2-substituted quinazolin-4(3H)-ones (236) in the presence of 10 mol% FeCl₃ at 100 °C temperature in DMF (dimethyl formamide) as a solvent under dioxygen atmosphere. The quinazolin-4(3H)-ones (236) were easily formed by reacting O-aminobenzamide (234) with various aryl acetic acids (235) that include both electron-rich and electron-poor groups on the aryl rings. In the current catalytic system, important functional groups such as OCH₃, NH₂, OH, NO₂, Br, and Cl all survived, and the desired products were generated in excellent yields (Scheme 78).

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Scheme 78

Iron-catalyzed aerobic oxidative functionalization of the C(sp³)-H interaction for the synthesis of 2-substituted quinazolin-4(3H)-ones.

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The C-H bonds have been oxidized to generate -hydroxycarboxylic acid through a radical route in the Fe/O₂ system, followed by dehydrogenation to provide 2-oxo-2-carboxylic acid, according to a probable reaction pathway for the current iron-catalyzed aerobic oxidative functionalization of C(sp³)-H bonds. Under atmospheric oxygen, the resultant aldehyde is generated which has caught by o-substituted anilines, resulting in N-heterocyclic compounds (Scheme 79) (Chen, 2015).

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Scheme 79

Mechanistic pathway for the synthesis of 2-substituted quinazolin-4(3H)-ones.

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Pyrido[4,3-d]pyrimidines show a variety of antimicrobial, antipyretic, antimicrobial, antiviral, anti-inflammatory, and antifungal characteristics are among the many biological actions of pyrimidines. A novel phenylpyrido[4,3-d] series is discovered, under solvent-free conditions. Pyrimidine-2-amine derivatives are synthesised by reacting (E-3,5-bis(benzylidene)-4-piperidones with guanidine carbonate in the presence of (Fe₂O₃-MCM-41-nPrNH₂ as a magnetically recoverable nano-catalyst. Magnetic iron oxide nanoparticles are particularly appealing due to their unique features and prospective uses in a variety of fields, including magnetically assisted medication delivery, MRI contrast agents, hyperthermia, and biomolecule magnetic separation (Hurlbert and Valenti, 1968; Althuis et al., 1979; Althuis, 1980; Mo, 2009; Elslager, et al., 1972; Rosowsky et al., 1995; El-Subbagh, 2000).

The reaction conditions for efficient synthesis of Pyrido[4,3-d]pyrimidines and its derivatives (239) through the two-component reactions in the presence of magnetically recoverable catalyst [(Fe₂O₃-MCM-41- nPrNH₂] between (E-3,5-bis(benzylidene)-4- piperidones (237) and guanidine carbonate (238) under solvent-free conditions. For the synthesis of phenylpyrido[4,3-d]pyrimidines (239), a range of aromatic aldehydes with both electron-rich and electron-deficient groups were used and the results showed that the reaction occurred well in all cases. It's worth noting that 3,5-dibenzylidene piperidin-4-one with electron-deficient groups reacted quickly, whereas those with electron-donating groups needed longer reaction periods. Electron-deficient groups on phenyl rings cause more electronic positive charge on the -atoms than electron-donating moieties (Scheme 80).

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Scheme 80

Iron catalyzed synthesis of 2-aminopyrimidine derivatives.

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The presented mechanism has been that the reactants easily transfer toward the nanocatalyst channels due to the two-dimensional pores of MCM-41, and they have been accompanied by the inherent hydrogen bonding of –OH and –NH₂ groups, both of which have been capable of bonding with the carbonyl oxygen of the 3,5-dibenzylidene piperidin-4-one (237) moiety to increase its electrophilicity. It has been necessary to convert guanidine carbonate to a free base in the presence of a base (NH₂ groups). The free base of guanidine carbonate (238) has been first added to 3,5-dibenzylidene piperidin-4-one (237) to produce intermediates (240), (241). Following that, the water has removed for the synthesis of the final product (239) (Scheme 81) (Rostamizadeh, 2013).

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Scheme 81

Mechanistic pathway for the synthesis of 2-amino pyrimidine derivatives.

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3.4 From nitriles

The azepine, which is present in a wide range of natural products and physiologically active compounds, has a broad substrate range and strongly functional group compatibility. A range of structurally unique and intriguing azepine derivatives are successfully synthesized in good to fair yield by combining iminyl radical-triggered 1,5-hydrogen atom transfer with (5 + 1) or (5 + 2) annulation procedures. This technique employs FeCl₂ as a catalyst and easily accessible oximes. Many useful substances may be easily produced from annulation products (Renfroe et al., 1984; Tomasi, 2010; Dudognon, 2018; Pellissier, 2011; Pellissier, 2018).

Oximes (242) and acrylonitrile (243) were reacted in the presence of FeCl₂ (10 mol%) as the catalyst, 1,4-dioxane as the solvent, and PivONa as the additive at 100 °C for 12 h to develop an effective catalytic system to realize the (5 + 2) annulation reaction for the synthesis of derivatives of azepine (244). FeCl₂ exhibited the best catalytic reactivity toward azepine (244) synthesis. Substrate (242) oxime reacted well with acrylonitrile (243), affording the desired products, and a variety of functional groups such as OCH₃, (CH₃)₃SiCl, ROR¹, CN, CF₃, OCF₃, Cl, I, Br, F, C_nH_2n were well tolerated. Several heterocycle-derived oximes, such as those produced from quinoline, benzodioxole, thiophene, pyridine, benzothiazole, isoquinoline, furan, and benzofuran, were also favourable to this method. Ethyl/ethyl and phenyl/methyl were examples of substituents (R¹ and R²) at the γ-position of the oxime moiety. Cyclic moieties were also used as substituents (Scheme 82).

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Scheme 82

(5 + 1) or (5 + 2) annulation procedures for the synthesis of azepine derivatives.

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Transfer of single-electron to the oxime from Fe^II occurs in N-O bond breaking, generating a Fe^III and an iminyl radical (245) in the cascades 1,5-HAT/(5 + 2) annulation process. The second undergoes 1,5- HAT, which causes the formation of an alkyl carbon radical (246). The synthesis of new carbon radical (247) by the addition of γ-carbon radical to the alkene. The carbon radical (247) would react with the intramolecular imine group to generate an intermediate (248), which could then be oxidized by Fe^III to form an iminium ion (249) while the Fe^II catalyst has been regenerated. The azepine derivative (244) would be produced after deprotonation. Fe^III salts can also cause the reaction, and one explanation for this could be because the Fe^III salts were converted to Fe^II species first under the reaction circumstances (e.g., 1,4- dioxane) (Scheme 83) (Liang, 2020).

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Scheme 83

Mechanistic pathway for the synthesis of azepine derivatives.

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Benzothiadiazine-1,1-dioxide and quinazolinone derivatives have a wide range of biological and therapeutic properties. Benzothiadiazine-1,1-dioxide derivatives (such as diazoxide) are proven to diminish AMPA receptor desensitisation and enhance defective synaptic transmission of functions, making them beneficial for the treatment of early stages Alzheimer's disease (De Tullio, 2005; Boverie, 2005; De Tullio, 2003; Coghlan et al., 2001; Braghiroli, 2002; Nagarajan, 2001; Tedesco, 2006). The cascade coupling processes allow for the effective iron-catalyzed production of quinazolinone and benzothiadiazole-1,1-dioxide derivatives. There is no need for an external ligand or additive FeCl₃ to be used as the catalyst and the starting substrates are widely accessible such as 2-halo benzenesulfonamides, 2-bromo benzoic acids, and amidine hydrochlorides (Tedesco, 2006; Ikawa, 2007).

The reaction conditions for the formation of 1,2,4-Benzothiadiazine-1,1-Dioxide (252) and quinazolinone derivatives (254) were substituted 2-halobenzene-sulfonamide (250), substituted 2-halo benzoic acid (253); respectively and amidine hydrochloride (251) were the substrates FeCl₃ (0.1 mmol) as a catalyst with Cs₂CO₃ and DMF for 12 h at the temperature of 120 °C under nitrogen atmosphere. For all of the substrates evaluated, under the optimum coupling procedures afforded the required 1,2,4-benzo thiadiazine-1,1-dioxide (252) derivatives in moderate to high yields. The aryl iodide converted to the intended product better than the aryl bromides for substituted 2-halo benzenesulfonamides. There were no considerable reactivity differences amongst the amidines studied in this coupling process. The electronic impact of substituted groups in 2-bromo benzoic acids, including electron-donating, -neutral, and -withdrawing substituents, had no noticeable reactivity variation. Amidines, both aliphatic and aromatic, produced excellent yields (Scheme 84) (Yang, 2009).

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Scheme 84

Iron-catalyzed production of quinazolinone and benzothiadiazole-1,1-dioxide derivatives.

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Natural compounds and medicines with exceptional biological activity have the 2-amino benzothiazole core as a preferred scaffold. Iron-catalyzed tandem reactions of 2-iodo anilines with isothiocyanates in water, leading to the synthesis of diverse 2-amino benzothiazoles. The transformation went efficiently in the presence of octadecyl trimethyl ammonium chloride as a phase-transfer catalyst (PTC), and the respective products are synthesized in moderate to high yields (Paget, 1969; Lours, 1970; Suter and Zutter, 1967; Shirke, 1990; Hays et al., 1994; Jimonet, 1999; Ding and Wu, 2007; Ding et al., 2009; Ding, 2007; Ding et al., 2008; Ding et al., 2007; Ding and Wu, 2008; Ding et al., 2009; Ding, 2009; Ding and Wu, 2008; Ding, 2010).

2-iodo aniline (255) and isothiocyanate (256) were reacted in the presence of a catalyst such as FeCl₃ (5 mol%) with the L₆ = 1,10-phenanthroline, PTC-4 (octadecyl trimethyl ammonium chloride), DABCO (1,4-diazabicyclo[2.2.2]octane), and H₂O at the temperature of 80 °C for the synthesis of 2-amino benzothiazoles (257). The method's range and specificity were demonstrated by altering the 2- iodo benzenamine, which could be easily produced from 4-substituted benzenamines, and the reactions yielded the appropriate 2-amino benzothiazole (257) in good to high yields. The results showed that numerous functional groups on the phenyl ring of 2-iodo benzenamine, such as CF₃, F, Cl, and CH₃, were well tolerated (Scheme 85) (Ding, 2010).

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Scheme 85

Iron-catalyzed tandem reaction for the synthesis of 2-aminobenzothiazoles.

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3.5 From alcohols

Pyrimidine's existence in a biological system as well as its widespread in synthetic chemistry, among the other nitrogen-containing compounds, show its importance. They can also be used in light-emitting devices as photoactive materials. A broad range of 2,4,6-trisubstituted pyrimidines is produced through dehydrogenative coupling of amidines with primary and secondary alcohols using a Fe^II-complex incorporating redox non-innocent 2-phenyl azo-(1,10-phenanthroline) ligand as a catalyst (Joule and Mills, 2012; Raw and Taylor, 2010; Park et al., 2017; Gao, 2017).

The pyrimidine derivatives (261) synthesis substrates were benzyl alcohol (259), 1-phenyl ethanol (258), and guanidine (260). In non-polar solvents such as toluene and xylene, the reaction proceeds well; however, polar solvents yield only traces or no product but t-BuOK was effective. The pyrimidine 261 was afforded at a good yield of 82% when the coupling of (258), (259), and (260) was carried out at 100 °C for 16 h in the presence of 0.5 equiv. of t-BuOK and 3.0 mol% of Fe₅. With a wide range of electron-rich, -deficient, and heteroaromatic functionalities on both 1° and 2° alcohols, the reaction proceeds smoothly (Scheme 86).

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Scheme 86

2,4,6-trisubstituted pyrimidines synthesis through the dehydrogenative coupling of amidines.

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The process begins with the dehydrogenation of 1° and 2° alcohols, which have been catalyzed by Fe₅. In a one-electron hydrogen atom transfer (HAT) reaction, the iron-stabilized azo-anion radical takes hydrogen atoms from the alcohol to generate a ketyl radical intermediate, which then undergoes quick one-electron oxidation to yield the corresponding carbonyls. The carbonyls generated in situ follow base-promoted condensation to form the α-β-unsaturated ketone, which has been converted to pyrimidines by base-mediated condensation with amidine and intramolecular cyclization (Scheme 87) (Mondal, 2020).

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Scheme 87

Mechanistic pathway for the synthesis of 2,4,6-trisubstituted pyrimidines.

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Quinoxaline is an N-heterocyclic chemical having benzene and pyrazine rings. Natural compounds and physiologically active compounds have quinoxaline structures in abundance. Quinoxaline moieties are found in a variety of commercial medications, including sulfaquinoxaline, quinacillin, clofazimine, and echinomycin. Transfer hydrogenative condensation of 2-nitro aniline with vicinal diols through the one-pot synthesis of quinoxalines by iron-catalyst. The Knolker complex such as tricarbonyl (h4-cyclopentadienone) iron, stimulated the reduction of nitroarenes and, oxidation of alcohols generating carbonyl and 1,2-diaminobenzene intermediates in situ. The iron complex is activated using trimethylamine N-oxide. For transfer hydrogenative condensation, a variety of unsymmetrical and symmetrical vicinal diols are being used, affording quinoxaline derivatives in excellent yield (Liu, 2020; Ajani, 2014; Parhi, 2013; Hajri, 2016; Zhao, 2019; Liang, 2020; Kothavale et al., 2019; Li, 2019).

The reaction conditions of transfer hydrogenative condensation for the quinoxalines,2-nitroaniline (268) were (0.4 mmol) and 1-phenylethane-1,2-diol (269), (0.8 mmol) react in the presence of an iron catalyst (Fe₆) (2 mol%), Me₃NO (4 mol%) and solvent (1 mL) in a sealed tube at 150 °C for 24 h to give the isolated yields of quinoxalines (270). Condensation proceeded by cyclization with 2-nitroaniline (268) generates 2-alkyl-substituted quinoxalines (270) in excellent yields from alkyl-substituted unsymmetrical vicinal diols (269). Electron-rich groups (CH₃ and OCH₃) with nitro aniline gave greater yields of quinoxalines than electron-withdrawing groups (Cl) with substrates. The hydrogenative condensation of symmetrical diols with 2-nitro aniline (268) by transfer hydrogenation. 2-nitro aniline (268) with electron-rich groups (CH₃ and OCH₃) gave high yields of the corresponding products. Although 2-nitro aniline with electron-deficient groups (Cl, Br, I, and CF₃) are less efficient than the electron-donating groups (Scheme 88).

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Scheme 88

One-pot synthesis of quinoxalines by iron-catalyst.

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The plausible mechanism for the transfer hydrogenative condensation of 2-nitro aniline (268) with vicinal diols (269); Me₃NO oxidizes a CO ligand on Knolker complex Fe₆ and liberates CO₂. The activated iron-catalyst has been produced, which mediates the oxidation of diols (269) to provide the intermediate of carbonyl and [Fe]–H₂. The α-hydroxyimine intermediate (272 or 273) has been produced via condensation of carbonyl compounds with 2-nitro aniline (268). The hydrogenation of nitro groups and oxidation of the residual alcohol through an iron-mediated transfer hydrogenation mechanism can then yield α-keto amine intermediates (274) or (275). Finally, the α-keto amine intermediate (274 or 275) passes through intramolecular condensation and aromatization, affording the desired products (Scheme 89) (Putta, 2021).

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Scheme 89

Mechanistic pathway for the synthesis of quinoxalines.

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Quinazolinone is a fundamental basis in natural compounds that have a wide variety of biochemical and pharmaceutical properties. The conversion of primary alcohols with o-amino benzamide into N-heterocycles, such as quinazolinone derivatives is effectively established using an iron-catalyzed one-step one-pot oxidative method. Both alkyl and aryl primary alcohols are reactive in the ecologically friendly methodology, which showed strong functional group compatibility.

The reaction conditions for the formation of quinazolinone (278) were various types of primary alcohols (276) and o-amino benzamide (277) as model substrates in the presence of catalyst FeCl₃ (2 mol%), an oxidant in decane such as tert-butyl hydroperoxide(TBHP), DMSO, under an air atmosphere, at 60 °C temperature for 7 h. Numerous primary alcohols (276) were explored using the optimal conditions. Good to fair yields were obtained for several substituted benzyl alcohols with electron-donors and deficient groups. 2-furyl methanol, a heteroaryl substrate, yields the corresponding product in an excellent (76%) yield. More difficult alkyl primary alcohols, such as octanol, were used to illustrate the system's broad synthetic applicability, and the desired products were obtained with fair yields (Scheme 90) (Zhao, 2014).

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Scheme 90

Synthesis of quinazolinone derivatives using an iron-catalyzed one-pot oxidative method.

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3.6 From amines

DBTD (3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides) is a key synthetic target in a wide range of physiologically active chemicals, psychoactive drugs, and artificial medicines. Using iron as the catalyst and air as the oxidant, a simple and one-pot synthesis of 3,4-dihydro-2H-1,2,4-benzothiadiazine1,1-dioxides by oxidative condensation of 2-amino benzenesulfonamide with benzylamines is generated. Under moderate conditions, this iron-catalyzed aerobic oxidative transformation has high efficiency, strong functional group tolerance, and broad substrate scope, and the use of air as the only oxidant makes this technique highly practical and cost-effective (Goffin, 2018; Impagnatiello, 1997; Bourasset, 2005; Phillips, 2002; Chen, 2010; Alukal and Lepor, 2016; Inagaki, 2013; Ravez, 2015).

The reaction conditions for the formation of 3,4-dihydro-2H-1,2,4- benzothiadiazine 1,1-dioxides (281) (DBTD) were 2-amino benzenesulfonamide (279) with a range of benzylamines (280) with catalyst FeBr₂(10 mol%) and chlorobenzene at 100 °C temperature under air atmosphere. Evaluating 2-amino benzenesulfonamide (279) with a variety of benzylamines (280) revealed the substrate scope for the production of numerous DBTD derivatives (281). The condensation of benzylamines (280) with electron-rich and electron-deficient substituents on the aromatic rings was carried out easily, affording the required products in excellent quantities. Under the reaction circumstances, various types of functional groups such as F, Cl, CH₃, OCH₃, and R-O-CH₂-O-R moieties were tolerated well. The reaction efficiency was unaffected by moving the OCH₃ group from the para to the meta and ortho positions. The bulky substrate 1-(1-naphthyl)methanamine, in addition to benzylamines (280), was also compatible with this reaction, generating the desired product in 74% yield (Scheme 91).

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Scheme 91

One-pot synthesis of 3,4-dihydro-2H-1,2,4-benzothiadiazine1,1-dioxides by oxidative condensation.

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The benzylamine (280) produces the homo-imine (282) by oxidative self-condensation, which has a probable mechanism for this oxidative process. The homo-imine (282) may then be readily transmitted using 2-amino benzenesulfonamide (279) to get amidoamine (283). At the same time, the aldehyde (284) produced in small amounts by the hydrolysis of imine (282) may condense with arylamines (280) and (279) to yield amidoamine (283). The required DBTD chemical (281) has been produced by intramolecular cyclization of aminoimine (283) obtained from (282), (284), and substrate (279) (Scheme 92) (Gopalaiah, 2019).

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Scheme 92

Mechanistic pathway for the synthesis of 3,4-dihydro-2H-1,2,4-benzothiadiazine1,1-dioxides.

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3.7 From alkenes

Aziridines are effective ligands for catalysis, pharmacophores, and flexible intermediates of bioactive materials and fine chemicals, hence aziridination processes are essential in the synthetic industry. Iron N,N′-dimethyl-N,N′-bis(2-pyridinylmethyl)cyclohexane-1,2-diamine-Fe(MCP)- and Fe(PDP)-type complexes catalyze an effective nitrogen-transfer process. The ligand's 2-pyridinylmethyl substitution does not affect reaction efficiency; however, modifications in the ligand are used to sterically protect the iron core which improves the reaction cycle. This aziridination reaction takes place under moderate circumstances and does not involve the addition of further olefin (Moragas, 2014; Ismail et al., 2009; Jarzyński, 2017; Ferioli, et al., 2005; Chen, 2013; Hu, 2004).

The alkene (285), PhINNs, as substrates for the synthesis of aziridines (286) in the presence of 5 mol% Fe₇ complex and CH₃CN at the temperature of 21 °C. Under the optimized conditions, limiting quantities of electronically varied styrenes react with moderate efficiency to generate racemic aziridines. The reaction tolerates a pendant acetate, nitrile, bromine atom, phenolic ether. Aziridination of isomerically pure cis-1-phenyl-1-propene proceeds with an erosion of the original olefin geometry (Scheme 93) (Shehata et al., 2018).

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Scheme 93

Iron catalyzed synthesis of Aziridines.

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Sulfone-containing oxindoles compounds have major functions in materials, chemical products, and medications. Sulfonyl substituted oxindoles, a new aerobic oxidative sulfonyl-carbocyclization of activated alkenes is developed. As a green oxidant, molecular oxygen is used, and it serves a critical role in beginning this transition, making the protocol relatively simple to follow. This sulfone integration process is ecologically friendly and practical since it uses easily accessible benzene sulfonic acids, an affordable iron salt catalyst, and air as the oxidant (Metzner and Thuillier, 2013; Renaud and Sibi, 2001).

The reaction conditions were N-methyl, N-aryl acrylamide (287) and benzenesulfinic acid by using 10% Fe(NO₃)₃·9H₂O as a catalyst in MeCN at the temperature of 100 °C for 12 h in the presence of air for the synthesis of sulfone-containing oxindoles (288). Using the improved reaction conditions, the substrate scope of this aerobic sulfon-carbocyclization of alkenes was expanded to include different N-aryl acrylamides (287). N-aryl acrylamides (287) with both electron-rich and electron-deficient groups at the aromatic ring performed well and produced good to high yields of the respective products. In general, substrates that have an electron-deficient group can provide greater yields. Under these moderate reaction conditions, halo-substituents (F, Cl, Br, and I) were well tolerated with the N-Methyl-N-phenyl methacryl amides (287) which provide good yields (88–96%) of the respective halo-substituted oxindoles (Scheme 94).

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Scheme 94

Aerobic oxidative sulfonyl-carbocyclization of activated alkenes for the synthesis of Sulfonyl substituted oxindoles.

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A plausible mechanism has been given; initially, O₂ could readily begin with the sulfonyl radical. Following radical addition to activated alkene (287), a radical intermediate has been formed. The radical intermediate (289) undergoes intramolecular carbocyclization to produce the radical intermediate (290), which has to be oxidized by Fe^III to produce the cationic intermediate (291) through the SET process. After a deprotonation process, intermediate (291) yields a terminal product (288). Fe^II might be easily oxidized to Fe^III in the presence of O₂ to fulfil the catalytic cycle (Scheme 95) (Shen, 2014).

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Scheme 95

Mechanistic pathway for the synthesis of Sulfonyl substituted oxindoles.

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Aziridines are found in a variety of pharmacological and natural medicines with strong biological activity, and they are useful building blocks for a variety of N-heterocycles. The aziridination of olefins with equimolar quantities of iminoiodinane is possible due to a catalytic system based on ionic liquid, ferrous triflate, and quinaldic acid (Padwa and Woolhouse, 1984; Kasai and Kono, 1992; Reddy et al., 2005; Surendra et al., 2005; Evans et al., 1994; Fioravanti, 1985).

The reaction conditions were styrene derivatives (292) react with sulfonamides (293) in the presence of Fe(OTf)₂ (5 mol%), quinaldic acid (294), and hydrophobic ethylmethylimidazolium bis[(trifluoromethyl)sulfonyl]- amide (emim BTA) (295) and CH₃CN at 85 °C temperature for the synthesis of aziridines (296). The iron-catalyzed aziridination process worked well with styrene derivatives as a substrate and produced products with good to high yields. P-methyl styrene and p-nitrostyrene produced the greatest results. The corresponding aziridines (296) were obtained in acceptable yields from p-acetoxy styrene, p-cyanostyrene, and p-trifluoromethyl styrene (Scheme 96) (Mayer et al., 2008).

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Scheme 96

Synthesis of aziridines by using iron as a catalyst.

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Imidazoles and their derivatives are an important class of N-heterocycles chemicals which have a wide range of pharmaceutically active drugs and natural products. Multi-substituted imidazoles are important to core structures in synthetic chemistry because of their unique biological activity, including antimicrobial, anticancer, antibiotic, antivirus, and anti-inflammatory properties. Because of its low cost, simple accessibility, stability, non-toxicity, and eco-friendliness, iron catalysts are significant and efficient catalysts in numerous organic processes (Heeres and Antimycotic imidazoles. Part 4. , 1979; Hunkeler, 1981; Hamdouchi, 1999; Nakano, 2000; Pan, 2010).

The reaction conditions for the synthesis of imidazoles (299) were benzamidine (297) and 1-(2-nitro vinyl)-benzene (298) as a substrate in the presence of FeCl₃(20 mmol%) catalyst and DMF at 90 °C for 4 h. The required compounds (299) were produced in good to high yields using a range of N-aryl benzamidines (297) as partners. High yields were found in benzamidines (297) with electron-rich substituents on R¹ and R². Electron-deficient substituted benzamidines, afforded low yields, with some (such as nitro) unable to produce the desired product. The yield was increased to 86 % when benzamidine contained two electron-rich groups (Scheme 97).

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Scheme 97

Iron catalyzed synthesis of imidazoles.

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The reaction's mechanism has been suggested as follows: Initially, the intermediate (302) was generated by adding N-p-tolyl benzamidine (300) to 1-(2-nitro vinyl)-benzene through Michael addition (298). The intermediate (303) was created from the (302) using FeCl₃ as a Lewis acid and another intramolecular nucleophilic addition. After eliminating nitroxyl (HNO) and H₂O, the end product (301) was produced from intermediate (303) (Scheme 98) (Liu et al., 2013).

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Scheme 98

Mechanistic pathway for the synthesis of imidazoles.

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3.8 From miscellaneous compounds

A novel iron aziridination catalyst is developed from the tetraimidazolium substrate (^Me,EtTC^Ph)(I)₄, which is supported by a macrocyclic tetracarbene ligand. In a “C₂ + N₁″ addition reaction, this iron complex catalyzes the aziridination of electron-rich aryl azides and a broad variety of substituted aliphatic alkenes, including tetrasubstituted ones. Without a noticeable decrease in yield, the catalyst can be recovered and utilized up to three times more (Kasai and Kono, 1992; Liu et al., 2007; Colandrea et al., 2003; Sharma, 2009; Loncaric and Wulff, 2001).

Synthesis of aziridines (306) required the following reaction conditions; a 0.1 mol% catalyst loading of Fe₈ (iron complex) with an excess of alkene (305), aryl azide (304), and without solvent. After 18 h at 90 °C, the reaction was complete (all of the organic azides had reacted), the reaction mixture was cooled to room temperature, and the catalyst was removed by filtration over Celite. The iron-catalyst effectively conducted aziridination with 1-decene and electron-deficient azides such as 1-azido-4-(trifluoromethyl)benzene. Both cis- and trans-substituted and disubstituted alkenes were found to be effective. With just 0.1% catalyst loading, the yield for 9-(p-tolyl)-9-azabicyclo[6.1.0]nonane was practically quantitative (97%). Because of the steric bulkiness of the propyl groups, the reaction with trans-4-octene was slow and generated less yield (Scheme 99).

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Scheme 99

C₂ + N₁″ addition reaction for the synthesis of aziridines by using iron complex.

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A prospective intermediate in this reaction mechanism has an iron^IV imide (308) in aziridination reactions with aryl azides (304). Iron imides in the 2⁺, 3⁺, and 4⁺ oxidation states are stabilized by three-fold-symmetric strong σ-donor ligands, however, these complexes do not react with alkenes to form aziridines (Scheme 100) (Cramer and Jenkins, 2011).

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Scheme 100

Mechanistic pathway for the synthesis of aziridines.

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Functionalized fullerenes, a family of high-performance nano-molecules, are finding numerous useful uses as supramolecular chemistry, adaptable building blocks in nanomaterials, pharmacology, and perovskite solar cells. For the synthesis of N-containing pyrrolidine- [2′,3′:1,2]fullerenes, an iron^II-catalyzed redox-neutral radical cascade reaction of (Liu, 2019) fullerene with, γ,δ-unsaturated oxime esters is used. The transformation occurs through intramolecular cyclization and has a straight forward operation, functional group compatibility, a large substrate scope, and is also suitable for scale-up synthesis, allowing access to a variety of free pyrrolidino[2′,3′:1,2]fullerenes (Prato, 1997; Giacalone et al., 2009; Guldi, 2009; Imahori, 2007; Zieleniewska, 2018; Megiatto et al., 2020; Nakamura and Sawamura, 2001; Castro, 2017; Nierengarten, 2017; Li et al., 2012; Cui et al., 2017; Matsuo, 2012; Wang, 2015; Maroto, 2014; Li, 2016; Aghabali, 2016; Ueda, 2016; Zhou and Wang, 2016; Li et al., 2017; Hussain, 2019; Maroto, 2015; Giron, 2018; Maggini et al., 1993; Gan, 1998; Gan, 1996; Komori, 1996; Koeppe, 2005; Yang, 2016; Shi, 2016).

The reaction conditions for the formation of pyrrolidine- [2′,3′:1,2]fullerenes (310) were O-acyl oxime (309) in the presence of FeCl₂·4H₂O as a catalyst in a co-solvent of o-dichlorobenzene (ODCB) and CH₃CN at various temperatures and time under a nitrogen atmosphere. The reaction conditions were used to test the redox-neutral cascade reaction of aryl and heteroaryl, γ,δ-unsaturated oxime esters tethered to a terminal olefinic unit. In good to high yields, all processes underwent cascade cycloaddition to produce desirable monosubstituted free pyrrolidino[2′,3′:1,2]fullerenes (310). The transition tolerated several functional groups that adorned the phenyl ring of oxime esters, such as OCH₃, Br, I, and CN groups. When substrates were compared with electron-deficient groups and electron-rich groups, electron-rich groups had higher reactivity and yielded the desired product in a higher yield at a lower reaction temperature which demonstrates that the electronic effect of the substituent has a clear impact on the reaction (Scheme 101).

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Scheme 101

Iron^II-catalyzed redox-neutral radical cascade reaction for the synthesis of functionalized fullerenes.

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A plausible mechanism has been given; the iminium radical (311) has been formed by the oxidative addition of Fe^II to the NO bond of O-acyl oximes (309), which then undergoes intramolecular cyclization to give intermediate (312). The fullerene radical (313) has been formed when radical intermediate (312) has been added to C₆₀. An intermolecular radical cyclization with an imine moiety occurs in route I, resulting in (314) intermediate. With the release of Fe^II, radical (314) has been oxidized by Fe^III produced in situ to create cationic species (315). Following that, adding FeCl₂·4H₂O hydrate water and/or concurrent water to (315) produces the unstable intermediate (316), which then changes into the end product (310). Another, less desirable path-II cannot be entirely ruled out in comparison to pathway-I. In pathway-II, the fullerene radical (313) has been oxidized by Fe^III to produce fullerene cation (317), which is then cyclized intermolecularly to produce iminium (318). After that, (318) goes through a similar hydrolysis procedure to get to (310). Furthermore, the process might occur in the presence of Fe^III salts, implying that iron with a higher oxidation state could be produced, however, the specific mechanism of the Fe^III-catalyzed reaction and the change in an oxidation state of Fe^III remain unknown (Scheme 102) (Wu, 2020).

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Scheme 102

Mechanistic pathway for the synthesis of functionalized fullerenes.

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Bioactive natural items, medicines, and functional materials all include aza-heterocycles. (Vitaku et al., 2014; Łowicki and Przybylski, 2022; Pyta, 2022)-triazines are synthesized in the presence of iron catalyst by [3 + 3]-annulation of N-alkyl aziridines with bicyclic diaziridines. 1,3-dipolar cycloadditions are involving these two saturated building elements which provide a simple technique for delivering a synthetic basis for heterocycle synthesis, and the iron catalyst is the focus of recent sustainable cycloaddition reactions due to its low toxicity, environmental friendliness, and low cost (Vitaku et al., 2014; Bolm, 2004; Correa et al., 2008; Bauer and Knölker, 2015; Nakamura and Yamamoto, 2004; D'Souza and Mueller, 2007; Blunt, 2012; Shang et al., 2017; Enthaler et al., 2008; Fürstner, 2009; Kennedy, 2019).

The reaction conditions for the formation of (Vitaku et al., 2014; Łowicki and Przybylski, 2022; Pyta, 2022)-triazines (322) were a series of diaziridines (320) with 1-(4-chlorobenzyl)-2-(p-tolyl)aziridine (321) as a standard substrate with FeCl₃ (10 mol%) as a catalyst in the presence of CH₂Cl₂ at room temperature for 5 min. Diaziridines (320) with both electron-donating and electron-withdrawing substituents at the 4-position of the aromatic rings, such as Br and OCH₃ groups, were effectively involved in the reaction and produced high yields of cycloadducts. The reaction of the heteroaromatic diaziridines proceeded without a problem, yielding good results. In addition, polycyclic-aromatic diaziridines (320) with 2-fluorene and 3,3-disubstituted diaziridine functionality were shown to be accessible and yielded well. These findings imply that different substitution patterns in diaziridines (320) can also be responded to (Scheme 103).

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Scheme 103

[3 + 3]-annulation of N-alkyl aziridines by iron catalyst.

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The chelation of unactivated aziridines (321) with FeCl₃ can lead to the synthesis of (323), which can lead to stereospecific ring-opening utilizing azomethine imine intermediate (323) to provide 324, which indicates a probable process for the formation of (Vitaku et al., 2014; Łowicki and Przybylski, 2022; Pyta, 2022)-triazines (322). The latter can result in intramolecular cyclization, resulting in the delivery of the desired heterocycles (322). During the interactions of aziridine with the azomethine imine (323), the resulting diastereoselectivity has been predominantly regulated by steric considerations. As a result, the sterically less inhibited approach the (path-A) favoured the synthesis of the trans-selective cycloadduct. Path-B, which might lead to cis-selectivity, has unfavored due to steric hindrance (Scheme 104) (Sarkar, 2020).

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Scheme 104

Mechanistic pathway for the synthesis of (Vitaku et al., 2014; Łowicki and Przybylski, 2022; Pyta, 2022)-triazines.

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